D2 antagonists, methods of synthesis and methods of use

ABSTRACT

Provided are D 2  or D 3  antagonist compounds and pharmaceutical compositions of formula I 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, or isomers thereof, wherein R 1 , R 2  and R 3  are as defined herein. The invention further comprises methods for making the compounds of the invention and methods for the treatment of conditions mediated by the dopamine D 2  or D 3  receptor from the compounds of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to provisional application No.61/356,096, filed Jun. 18, 2010, which is incorporated in its entiretyby reference herein.

FIELD OF THE INVENTION

This invention relates to novel dopamine D₂ and D₃ antagonists that areuseful as anti-nausea medicaments. The compounds are1,3,8-triazinspiro[4,5]decane-4-ones that are substituted at the N1, N3,or the N8 positions with various substituents discussed in detail inthis application.

SUMMARY

One aspect of the subject invention is a compound of formula I

or pharmaceutically acceptable salts thereof, or isomers thereof,wherein

R₁ is chosen from the group consisting of

-   (2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)(C₂-C₄alkyl) optionally    substituted at the 3 position with cyclopropyl or at the 6 position    with chlorine,-   (2-oxobenzo[d]oxazol-3(2H)-yl)(C₂-C₄alkyl),-   (2-oxobenzo[d]thiazol-3(2H)-yl)(C₂-C₄alkyl),-   (2-oxoindolin-1-yl)(C₂-C₄alkyl) optionally substituted at the    3-position with one or two components chosen from methyl or fluoro,-   (3-spirocyclopropane-(2-oxoindolin-1-yl))(C₂-C₄alkyl),-   (2-oxoindolin-3-yl))(C₂-C₄alkyl),-   phenyl(C₁-C₆alkyl),-   1-hydroxy-1-phenylmethyl(C₂-C₆ alkyl),-   1-acetoxyoxy-1-phenylmethyl(C₂-C₆ alkyl),-   bis(4-fluorophenyl)methyl-(C₁-C₆alkyl),-   (1H-benzo[d][1,2,3]triazol-1-yl)(C₂-C₄alkyl),-   1-phenyl-1-oxo-(C₂-C₆alkyl) optionally substituted at the 4 position    of the phenyl with halo,-   2,3-dihydrobenzo[b][1,4]dioxine-2-(C₂-C₄alkyl),-   1-(thiophen-2-yl)-1-oxo-(C₁-C₆alkyl),-   3-oxo-2H-benzo[b][1,4]oxazin-4-yl-(C₂-C₄alkyl),-   (2-(cycloalkyl)-1H-benzo[d]imidazol-1-yl)(C₂-C₄alkyl),-   ((3-((C₁-C₆alkyl)carbonyloxy(methyl))-2-oxo-2,3-dihydro-1H-benzo[d]Imidazol-1-yl))(C₂-C₄    alkyl),-   ((3-(methoxycarbonylethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl))(C₂-C₄    alkyl),-   ((2-(t-butoxycarbonyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl))(C₂-C₄    alkyl),-   1H-indazol-3-yl(C₂-C₄ alkyl),-   (1-(indolin-1-yl)-1-oxo)(C₂-C₄alkyl),-   ((3-(C₁-C₆alkyl)oxycarbonyl(C₁-C₆alkyl))-1H-indol-1-yl)(C₂-C₄alkyl),    or-   (2-(C₁-C₆alkyl)oxycarbonyl-1H-indol-1-yl)(C₂-C₄alkyl);

R₂ is phenyl optionally para-substituted with chloro, fluoro or methoxy,linear or branched C₂-C₆ alkyl, cycloalkyl of three to seven carbonatoms optionally substituted with one to six halogens; and

R₃ is

wherein n is 3-5,

andR₁₀ is H or alkyl of one to six carbons.

In one aspect, R₁ is not C₁-C₆ alkyl.

Another aspect of the invention provides a process for treating adisease that is respondent to dopamine D₂ or D₃ receptor antagonisttherapy by administering a compound of this invention to a patient inneed thereof.

Another aspect of this invention comprises a pharmaceutical compositioncontaining a compound of this invention in combination with apharmaceutically acceptable excipient.

In another aspect, the invention provides methods of preparing thecompounds of interest, as well as intermediates useful in preparing thecompounds of interest.

DETAILED DESCRIPTION

In one aspect, the invention provides compounds of formula I

or pharmaceutically acceptable salts thereof, or isomers thereof,whereinR₁ is chosen from the group consisting of

-   (2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)(C₂-C₄alkyl) optionally    substituted at the 3 position with cyclopropyl or at the 6 position    with chlorine,-   (2-oxobenzo[d]oxazol-3(2H)-yl)(C₂-C₄alkyl),-   (2-oxobenzo[d]thiazol-3(2H)-yl)(C₂-C₄alkyl),-   (2-oxoindolin-1-yl)(C₂-C₄alkyl) optionally substituted at the    3-position with one or two components chosen from methyl or fluoro,-   (3-spirocyclopropane-(2-oxoindolin-1-yl))(C₂-C₄alkyl),-   (2-oxoindolin-3-yl))(C₂-C₄alkyl),-   phenyl(C₁-C₆alkyl),-   1-hydroxy-1-phenylmethyl(C₂-C₆ alkyl),-   1-acetoxyoxy-1-phenylmethyl(C₂-C₆ alkyl),-   bis(4-fluorophenyl)methyl-(C₁-C₆alkyl),-   (1H-benzo[d][1,2,3]triazol-1-yl)(C₂-C₄alkyl),-   1-phenyl-1-oxo-(C₂-C₆alkyl) optionally substituted at the 4 position    of the phenyl with halo,-   2,3-dihydrobenzo[b][1,4]dioxine-2-(C₂-C₄alkyl),-   1-(thiophen-2-yl)-1-oxo-(C₁-C₆alkyl),-   3-oxo-2H-benzo[b][1,4]oxazin-4-yl))(C₂-C₄alkyl),-   (2-(cycloalkyl)-1H-benzo[d]imidazol-1-yl)(C₂-C₄alkyl),-   ((3-((C₁-C₆alkyl)carbonyloxy(methyl))-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl))(C₂-C₄    alkyl),-   ((3-(methoxycarbonylethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl))(C₂-C₄    alkyl),-   ((2-(t-butoxycarbonyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl))(C₂-C₄    alkyl),-   1H-indazol-3-yl(C₂-C₄ alkyl),-   (1-(indolin-1-yl)-1-oxo)(C₂-C₄alkyl),-   ((3-(C₁-C₆alkyl)oxycarbonyl(C₁-C₆alkyl))-1H-indol-1-yl)(C₂-C₄alkyl),    or-   (2-(C₁-C₆alkyl)oxycarbonyl-1H-indol-1-yl)(C₂-C₄alkyl);    R₂ is phenyl optionally para-substituted with chloro, fluoro or    methoxy, linear or branched C₂-C₆ alkyl, cycloalkyl of three to    seven carbon atoms optionally substituted with one to six halogens;    and

R₃ is

wherein n is 3-5,

andR₁₀ is H or alkyl of one to six carbons.

One aspect of the invention is a subgroup of these compounds wherein R₁is (2-oxoindolin-1-yl)(C₂-C₄alkyl) optionally substituted at the3-position with one or two components chosen from methyl or fluoro,(3-spirocyclopropane-(2-oxoindolin-1-yl))(C₂-C₄alkyl),(2-oxoindolin-3-yl))(C₂-C₄alkyl), or 1-phenyl-1-oxo-(C₂-C₆alkyl)optionally substituted at the 4 position of the phenyl with halo.

Another aspect of the invention includes those compounds wherein R₃ isrepresented by formula A, C, D, or F and R₁₀ is H.

Another aspect of the invention includes the compounds wherein R₃ isrepresented by formula A or D.

Another aspect of the invention includes the compounds wherein R₂ isphenyl or cyclohexyl.

Another aspect of the invention includes the compounds wherein R₂ iscyclohexyl.

Another aspect of the invention includes the compounds wherein R₂ isphenyl.

Another aspect of the invention includes the compounds wherein R₁ is notC₁-C₆ alkyl.

Another aspect of the invention includes the compounds wherein R₁ is(2-oxoindolin-1-yl) propyl optionally substituted at the 3-position withone or two components chosen from methyl or fluoro,(3-spirocyclopropane-(2-oxoindolin-1-yl))propyl,(2-oxoindolin-3-yl))propyl, or 1-phenyl-1-oxo-propyl optionallysubstituted at the 4 position of the phenyl with halo.

Another aspect of the invention includes the compounds wherein

R₁ is (2-oxoindolin-1-yl)propyl optionally substituted at the 3-positionwith one or two components chosen from methyl or fluoro,(3-spirocyclopropane-(2-oxoindolin-1-yl))propyl,(2-oxoindolin-3-yl))propyl, or 1-phenyl-1-oxo-propyl optionallysubstituted at the 4 position of the phenyl with halo;

R₂ is phenyl or cyclohexyl; and

R₃ is represented by formula A, C, D, or F and R₁₀ is H.

Another aspect of the invention includes the compounds wherein R₁ is(2-oxoindolin-1-yl) propyl and R₂ is cyclohexyl.

Another aspect of the invention includes the compounds wherein R₃ isrepresented by formula A.

Specific compounds falling within the scope of this invention include,without limitation:

Compound 6 (Example 2) Methyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 7 (Example 3)Methyl5-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)pentanoate Compound 8 (Example 4) Ethyl4-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)butanoate Compound 11 (Example 5)3-((4-Oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 13 (Example 6)Methyl5-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-5-phenylpentanoate Compound 14(Example 7) Methyl2-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 15 (Example 8)Methyl4-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 16 (Example 9)2-(Dimethylamino)ethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateCompound 17 (Example 10)4-((4-Oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 18 (Example 11)(S)-sec-Butyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 19(Example 12)2-((4-Oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 20 (Example 13)1-Methylpiperidin-4-yl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateCompound 21 (Example 14) Benzyl6-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)hexanoate Compound 22 (Example 15)6-(4-Oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)hexanoic acid Compound 24 (Example 16)2-(Dimethylamino)-2-oxoethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateCompound 25 (Example 17) 2-Morpholinoethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateCompound 26 (Example 18) (R)-Quinuclidin-3-yl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateCompound 30 (Example 19) 2-(Diethylamino)-2-oxoethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateCompound 31 (Example 20) 2-Amino-2-oxoethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateCompound 32 (Example 21) 2-Oxo-2-(piperidin-1-yl)ethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateCompound 33 (Example 22) (S)-methyl2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate Compound 34(Example 23) (R)-methyl2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate Compound 35(Example 24) 2-(4-Methylpiperazin-1-yl)-2-oxoethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoatCompound 39 (Example 25)(R)-2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetic acid Compound 40 (Example 26)(S)-2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetic acid Compound 42 (Example 27)Methyl3-((1-(4-fluorophenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 43(Example 28)3-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound45 (Example 29) (S)-Quinuclidin-3-yl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateCompound 46 (Example 30) Methyl3-((4-oxo-8-(3-(2-oxobenzo[d]oxazol-3(2H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 47 (Example 31)Methyl3-((4-oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 48 (Example 32)methyl 3-((8-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 49 (Example 33)3-((8-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazpiro[4.5]decan-3-yl)methyl)benzoic acid Compound 50 (Example 34) methyl3-((8-(3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 52(Example 35)3-((4-Oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 55 (Example 36)Methyl3-((1-(4-methoxyphenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 56(Example 37)3-((1-(4-Methoxyphenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound57 (Example 38) methyl3-((8-(3-(1H-indol-3-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 58 (Example 39)3-((8-(3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 59(Example 40)3-((8-(3-(1H-indol-3-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 60 (Example 41) tert-Butyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 61(Example 42) tert-butyl3-((8-(3-(3-(heptanoyloxymethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateCompound 62 (Example 43) tert-butyl3-((1-cyclohexyl-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 64(Example 44) Benzyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 69 (Example45)5-(4-Oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-5-phenylpentanoic acid Compound 70 (Example46)3-(4-Oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-3-phenylpropanoic acid Compound 71 (Example47)3-((4-Oxo-8-(3-(3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 72 (Example 48)3-((1-cyclohexyl-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, formate Compound74 (Example 49)3-((8-(heptanoyloxymethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, formate Compound 76 (Example 50)3-((8-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 77 (Example 51)3-((8-(4,4-(4-fluorophenyl)butyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 82 (Example 52)3-((1-(4-Methoxyphenyl)-4-oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 82 (Example 53)3-((8-(3-(1H-Indazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 83 (Example 54) methyl3-((1-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-phenyl-2,8-diazaspiro[4.5]decan-2-yl)methyl)benzoate Compound 85 (Example 55)3-((8-(3-(1H-Benzo[d][1,2,3]triazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 89 (Example 56)3-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, hydrochloride Compound 91 (Example 57)3-((8-(4-(4-methoxyphenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazpiro[4.5]decan-3-yl)methyl)benzoic acid Compound 92 (Example 58) tert-butyl3-((8-(3-(3,3-difluoro-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 93 (Example 59)tert-butyl3-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 94 (Example 60)3-((8-(3-(3,3-difluoro-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 100 (Example 61)3-((8-(3-(6-Chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 102(Example 62)2-Methyl-2-(4-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenoxy)propanoic acidCompound 108 (Example 63) tert-Butyl3-((8-(3-(1H-indazol-3-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate Compound 110 (Example 64)3-((8-(3-(2-(tert-Butoxycarbonyl)-1H-indol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 120 (Example 65)3-((8-(3-(3-Cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 123(Example 66)3-((8-(3-(3,3-Dimethyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 126 (Example 67)3-((8-(3-(3-(3-methoxy-3-oxopropyl)-1H-indol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 130 (Example 68)3-((4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, hydrochloride saltCompound 131 (Example 69)3-((4-Oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 137 (Example 70)2-((8-(3-(3,3-Dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 138 (Example 71)3-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound142 (Example 72)3-((4-oxo-1-phenyl-8-(4-phenylbutyl)-1,3,8-triazpiro[4.5]decan-3-yl)methyl)benzoicacid, formate Compound 143 (Example 73)3-((4-oxo-8-(4-oxo-4-(thiophen-2-yl)butyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, hydrochloride Compound 145 (Example 74)3-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 146 (Example 75)3-((8-(3-(3-methyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 148 (Example 76)2-((4-Oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 149 (Example 77)2-((4-Oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 150 (Example 78)3-((1-cyclohexyl-8-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, hydrochloride Compound 153 (Example 79)2-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 153 (Example 80)2-((8-(3-(3,3-Dimethyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 154 (Example 81)2-((4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 155 (Example 82)2-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 156(Example 83)3-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acidCompound 157 (Example 84)3-((8-(4-(4-fluorophenyl)-4-(methoxyimino)butyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, hydrochloride Compound158 (Example 85)3-((1-(4-fluorophenyl)-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 159 (Example 86)2-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acidCompound 160 (Example 87)3-((4-oxo-8-(3-(2-oxoindolin-3-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, hydrochloride Compound 161 (Example 88)2-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound162 (Example 89)2-((8-(3-(3-Fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 163 (Example 90)2-((8-(3-(3-Fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 164 (Example 91)3-((8-(3-(3-Fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid Compound 166 (Example 92)(R)-2-(4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetic acid Compound 167 (Example 93)(R)-2-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetic acid Compound 168 (Example 94)(S)-2-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetic acid Compound 170 (Example 95)(S)-2-(4-oxo-8-(3-(2-Oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetic acid Compound 171 (Example 96)4-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, hydrochloride Compound172 (Example 97)4-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, hydrochloride Compound 173 (Example 98)3-((8-(4-hydroxy-4-phenylbutyl)-4-oxo-1-phenyl-1,3,8-triazpiro[4.5]decan-3-yl)methyl)benzoic acid Compound 176 (Example 99)3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, hydrochloride Compound 177 (Example 100)3-(4-Oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoicacid Compound 179 (Example 101) Methyl3-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazpiro[4.5]decan-3-yl)benzoate Compound 180 (Example 102)2-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoicacid Compound 182 (Example 103)4-(4-Oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoicacid, hydrochloride Compound 186 (Example 104)N-(4-((4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide Compound 211 (Example 105)N-(3-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide Compound 212 (Example 106)N-(3-((4-Oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamideCompound 213 (Example 107)N-(3-((4-Oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide Compound 214 (Example 108)N-(4-(8-(4-(4-Fluorophenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazpiro[4.5]decan-3-yl)phenyl)methanesulfonamide Compound 215 (Example 109)N-(4-(4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)phenyl)methanesulfonamide Compound 216 (Example 110)N-(4-(4-Oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)phenyl)methanesulfonamide Compound 217(Example 111)N-(4-(8-(3-(3,3-Dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)phenyl)methanesulfonamide. Compound 218(Example 112)2-((1-Cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid, hydrochloride

The preceding compound names, as well as the compound names in theexamples below, were generated using either ChemDraw Ultra version 8.03or ChemBioDraw Ultra version 10, both of which are available fromCambridgesoft Corporation, as well as ACD Namepro software, version 6.0,or the AutoNom plugin for MDL Draw 2.1.

Utility and Administration

Motility functions of the gastrointestinal tract require interactions ofinhibitory and stimulatory processes controlled by the vagus nerve andmyenteric plexus. An inhibitory mechanism that appears to play a part indelayed gastric emptying is stimulation of the dopamine receptors.Dopamine D₂ and/or D₃ receptor stimulation increases fundic relaxation,diminishes peristalsis, decreases gastric tone, and a causes a loss ofcoordination between gastric and duodenal contractile activity. Dopamineitself also stimulates receptors in brain regions that can induce nauseaand vomiting.

Gastroparesis is a condition of decreased gastric motility characterizedby delayed gastric emptying in the absence of mechanical outletobstruction. Four to seven million people in the United States sufferfrom some degree of gastroparesis. The most distressing symptoms ofsevere gastroparesis are nausea and vomiting following a meal. Othersymptoms include heartburn and regurgitation despite treatment,abdominal bloating, early satiety, and abdominal pain. The use ofprokinetic agents can restore gastric motility and normalize theabsorption of food and may play an important part in facilitatingeuglycemia. Alleviating the distressing symptoms of nausea and vomitingcan improve patients' lives by correcting fluid, electrolyte balance andnutritional deficiencies.

Post-operative nausea and vomiting (PONV) is one of the most common anddistressing side effects associated with surgical procedures, withreported rates of 37% of nausea and 20% for vomiting (Quinn A C, Brown JH, Wallace P G, Asbury A J; Anaesthesia 49, 62-65 (1994)). It is acomplication dreaded by many patients that can lead to medicalcomplications and impose an economic burden. Gastrointestinal atony is acommon phenomenon contributing to vomiting in post-operative patients.The medical complications of PONV include an increased risk of pulmonaryaspiration of vomitus or fluid but also possible wound complication,gastric herniation, esophageal tears and muscular fatigue. Dehydrationand electrolyte imbalance can occur if PONV is severe, which can be anissue with young children. Finally, another concern may be the delayedability to take oral therapy and nutrition.

PONV may be caused by the use of analgesics as well as by after-effectsof anesthetic gases, which are not completely excreted for many hoursfollowing recovery.

Several classes of drugs constitute the backbone of antiemetic therapy,from older drugs like droperidol and metoclopramide to 5-HT₃ receptorantagonists, which were the focus of many studies and clinical trials inthe 1990s. However, only modest progress has been made in reducing theincidence of PONV despite extensive research and the use of variousclasses of antiemetic drugs (i.e. butyrophenones, domperidone,benzamides such as metoclopramide, histamine receptor antagonists suchas ondansetron, muscarinic receptor antagonists, glucocorticoids, NK1receptor antagonists),

Despite the antiemetic drugs available, PONV still has a high incidence.Similarly, despite the gastric motility drugs available, gastroparesisand gastropathies in general are still significant medical problems.Thus, we have found that there is still a significant medical need forefficacious and safe drugs for PONV, gastroparesis and other maladiesmediated via the D₂ receptor.

The compounds of this invention exhibit activity as dopamine D₂ receptorantagonists and/or D₃ receptor antagonists and thus are useful fortreating conditions in humans that are regulated by the dopamine D₂and/or D₃ receptor. A D₂ and/or D₃ antagonist is a compound, such asthose described herein, that binds to the appropriate receptor but thatdoes not provoke a biological response itself. Instead it blocks ordampens an agonist-mediated response. Thus, the compounds of thisinvention are useful for the treatment of a disease that is respondentto dopamine D₂ and/or D₃ receptor antagonist therapy by administering acompound of this invention to a patient in need thereof. Generally suchreceptor antagonist activity results in increased gastrointestinalactivity and normalized gut function. The compounds find particularapplicability as an anti-emetic, a drug that is effective in reducingnausea and vomiting that may be induced by motion sickness,gastroenteritis, use of opioid analgesics, and chemotherapy in thetreatment of cancer.

Non-limiting examples of conditions that might be treated with acompound of this invention include gastroparesis, gastric stasis,irritable bowel syndrome, functional dyspepsia, improvement of diabeticmetabolic control, gastro-esophageal reflux disease, heartburn,constipation, post-operative ileus, opioid-induced ileus, visceralhypersensitivity, post-prandial distress syndrome and othergastrointestinal disorders. Other conditions for which the antagonistsof this invention can be useful include post-operative nausea andvomiting, chemotherapy-induced nausea and vomiting, cyclic vomitingsyndrome, gastritis, gastroenteritis induced nausea and vomiting,hyperemesis gravidarum, symptoms related to migraine, and symptomsrelated to Parkinson's disease (or Parkinson's disease therapies),idiopathic nausea and vomiting, functional gallbladder disorder,functional biliary sphincter of Oddi disorder, and functional pancreaticsphincter of Oddi disorder, diarrhea, and treatment of drug dependence,among others. D₂ dopamine receptor antagonists of this invention canalso be used to increase milk production in lactating women and for the.

The compounds of the invention may also be useful in increasinggastroprokinetic activity, improving gastric emptying, reducing gastricdysrhythmias (normalization of gastrointestinal electrical activity),reduction of dyspeptic symptoms, relieving upper abdominal fullness(epigastric fullness), reducing early satiety, bloating, includingpostprandial bloating, belching, abdominal pain, epigastric pain(syndrome), regurgitation as well as reversal of hyperglycemicinhibitory activity on gastrointestinal motility.

The compounds of the invention may be administered in combination withgastrointestinal prokinetics, nonlimiting examples includingprucalopride, naronapride, cisapride, mosapride, velusetrag, andtegaserod. Antinausea and antiemetic activity makes coadministrationvaluable with analgesics susceptible to nausea and vomitingcomplications such as fentanyl, tramadol, sufentanil, alfentanil,remifentanil, carfentanil, lofentanil and opiates in general.

Compounds of the invention may be useful for use in diagnosticprocedures, for example endoscopy, by relaxation of the stomach fundus

Compounds of the invention may be useful for other indications such asschizophrenia and bipolar disorder.

To determine D₂ antagonist activity, one of ordinary skill may do sousing in vivo or in vitro tests. A standard in vitro test is set forthin Example 1 of this patent application. Results of such tests onrepresentative compounds of this invention are set forth therein. Invivo tests can be performed in the shrew in accordance with theprocedure set forth by Darmani, et. al. in J. Neural Transm (1999) 106:1045-1061. In vivo tests in dogs can be performed in accordance with theprocedure set forth Depoortère R, Barret-Grévoz C, Bardin L,Newman-Tancredi A. Apomorphine-induced emesis in dogs: differentialsensitivity to established and novel dopamine D2/5-HT(1A) antipsychoticcompounds. Eur J Pharmacol. 2008 Nov. 12; 597(1-3):34-8.

To determine D₃ antagonist activity, one of ordinary skill may do sousing in vivo or in vitro tests. A standard in vitro test is aradioligand binding assay carried out using the cloned human dopamine D₃receptor expressed in Chinese hamster ovary (CHO) cell membranes asdescribed by MacKenzie et al. 1994 (see Eur J Pharmacl. 1994 Jan. 1;266(1):79-85). In this assay test articles are incubated with D₃receptor membranes in the presence of [³H]methyl-spiperone for 60minutes at room temperature followed by filtrations and counting offilters by liquid scintillation spectroscopy. IC₅₀ values are determinedfrom displacement of [³H]methyl-spiperone and corresponding constants(Ki) are calculated according to the methods of Cheng and Prusoff 1973(see Biochem Pharmacol 22 (23):3099-3108, 1973). In vivo tests can beperformed in accordance with the procedure set forth by Darmani, et al.in J. Neural Transm(1999) 106: 1045-1061. For a discussion of clinicalrelevance, see Levant, B. The D3 Dopamine Receptor: Neurobiology andPotential Clinical Relevance. Pharmacological Reviews Sep. 1, 1997 vol.49 no. 3 231-252.

The compounds of this invention are are particularly valuable in thatthey generally have fewer side effects that may create problems for thepatient being treated. For example, it is useful if a compound beingadministered exhibits reduced mu opioid receptor binding activity. Themu opioid receptor is the primary site of action for most commonly usedopioids such as morphine, fentanyl, and the like. Compounds of thisinvention that show reduced mu opioid binding will not interfere withthe action of the opioid to reduce pain. Such binding activity may bedetermined by one of ordinary skill in the art by using in vivo or invitro tests. An example of an in vitro test may be found at Zhang S,Tong Y, Tian M, Dehaven R N, Cortesburgos L, Mansson E, Simonin F,Kieffer B, Yu L. Dynorphin A as a potential endogenous ligand for fourmembers of the opioid receptor gene family. J Pharmacol Exp Ther. 1998July; 286(1):136-41. An example of an in vivo test may be found atD'Amour F E, Smith D L (1941). A method for determining loss of painsensation. J. Pharmacol. Exp. Ther., 72: 74. An example of a group ofcompounds of this invention having such reduced opioid activity includesthose where the R₂ group is cyclohexyl.

Another side effect that is avoided using the compounds of thisinvention is referred as QTc prolongation. QTc prolongation ischaracterized by the prolongation of the QT interval onelectrocardiograph (ECG) and a propensity to ventriculartachyarrhythmias, which may lead to cardiac arrest and death. It isfound that some marketed anti-emetic compounds and compounds to treatgastroparesis, such as domperidome, exhibit such activity and can causesudden cardiac death, which is thought to result from the repolarizationof the ventricle of the heart that leads to atrial fibrillation.Compounds of the invention can be tested for QTc prolongation using invivo or in vitro testing. Examples in the literature for such testingcan be found at Yan G X, Shimizu W, Antzelevitch, C: Characteristics anddistribution of M cells in arterially perfused canine left ventricularwedge preparations: Circulation 1998; 98:1921-1927 and also Kirsch G E,Trepakova E S, Brimecombe J C, Sidach S S, Erickson H D, Kochan M C,Shyjka L M, Lacerda A E, Brown A M: Variability in the measurement ofhERG potassium channel inhibition: Effects of temperature and stimuluspattern. J Pharmacol Toxicol Methods 2004; 50: 93-101.

Another side effect that is sometimes seen in known compounds thatexhibit D2 and/or D3 activity is CNS penetration, which not desirablebecause it can lead to dyskinesia and dystonia (Parkinson's disease-likesymptoms). Benzimidazole/benzamide derivatives such as metoclopramideand domperidone, exhibit such activity, with the former penetrating theCNS more readily than the latter. The compounds of this invention showreduced CNS penetration. Compounds of the invention can be tested forCNS penetration using in vivo or in vitro testing. Examples in theliterature for such testing can be found at Yu S, Li S, Yang H, Lee F,Wu J T, Qian M G. A novel liquid chromatography/tandem mass spectrometrybased depletion method for measuring red blood cell partitioning ofpharmaceutical compounds in drug discovery. Rapid Commun Mass Spectrom.2005; 19(2):250-4.

The subject invention further provides treatment for the above listedmaladies comprising the administration of a therapeutically effectiveamount of one or more compounds of the invention to an individual inneed of treatment. Accordingly, the subject invention providespharmaceutical compositions of these compounds. In a preferredembodiment the patient is a human; however, non-human animals also canbe treated.

The compounds of the invention set forth herein may be administeredorally (PO), intravenously (IV), subcutaneously (SC/SQ), intramuscular(IM), rectally (PR), sublingually (SL) and parenteral, more generally,routes of delivery and via immediate release (IR) and controlled release(CR) formulations. Compounds of the invention may be administered indosage unit formulations containing conventional non-toxicpharmaceutically acceptable excipients such as carriers, adjuvants,vehicles and the like. The term parenteral as used herein includespercutaneous, subcutaneous, intravascular (e.g., intravenous),intramuscular, or intrathecal injection or infusion techniques and thelike. In addition, there is provided a pharmaceutical formulationcomprising a compound of this invention and a pharmaceuticallyacceptable excipient. One or more compounds of the invention may bepresent in association with one or more non-toxic pharmaceuticallyacceptable carriers and/or diluents and/or adjuvants, and if desiredother active ingredients. The pharmaceutical compositions containingcompounds of the invention may be in a form suitable for oral use, forexample, as tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsion, hard or soft capsules, orsyrups or elixirs.

Formulations are described in detail in a number of sources that arewell known and readily available to those skilled in the art. Forexample, Remington's Pharmaceutical Science by E. W. Martin describesformulations that can be used in connection with the subject invention.In general, the compositions of the subject invention will be formulatedsuch that an effective amount of the bioactive compound(s) is combinedwith at least one suitable carrier, solvent, excipient, and/or adjuvantin order to facilitate effective administration of the composition.

In accordance with the invention, pharmaceutical compositionscomprising, as an active ingredient, an effective amount of one or moreof the compounds of the invention and one or more non-toxic,pharmaceutically acceptable carrier(s) and/or diluent(s). Examples ofsuch carriers for use in the invention include ethanol,dimethylsulfoxide, glycerol, silica, alumina, starch, and equivalentcarriers and diluents.

Further, acceptable carriers can be either solid or liquid. Solid formpreparations include powders, tablets, pills, capsules, cachets,suppositories and dispersible granules. A solid carrier can be one ormore substances that may act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents or an encapsulating material.

The disclosed pharmaceutical compositions may be subdivided into unitdoses containing appropriate quantities of the active component. Theunit dosage form can be a packaged preparation, such as packetedtablets, capsules, and powders in paper or plastic containers or invials or ampoules. Also, the unit dosage can be a liquid basedpreparation or formulated to be incorporated into solid food products,chewing gum, or lozenge.

The term “individual(s)” is defined as a single mammal to which isadministered a compound of the present invention. The mammal may be arodent, for example a mouse or a rat, or a non-rodent, for example apig, a horse, a rabbit, a goat, a cow, a cat, a dog, or can be a human.In a preferred embodiment, the individual is a human.

Process for Making the Compounds

Compounds of this invention are prepared by following standard chemicalreactions based on the teachings of this invention, once the novelcompounds set forth herein are defined.

Compounds of this invention can be prepared in accordance with one ormore of the Schemes discussed below. All of the starting materials areeither commercially available or can be prepared by procedures thatwould be well known to one of ordinary skill in organic chemistry. Theproducts may be used as collected or may first be purified usingconventional techniques such as preparative TLC or HPLC, chromatography,precipitation, crystallization and the like.

Scheme I illustrates the construction of the1,3,8-triazaspiro[4.5]decan-4-one ring system bearing a N₁ (cyclo)alkylor aryl R₂ group, a N₃ alkyl or aryl carboxylic acid containing R₃group, and a N₈ (hetero)arylalkyl R₁ group. The N₁ substituent isintroduced via Strecker reaction of an appropriately R₂-substitutedamine, N-benzyl-4-piperidone, a cyanide source such as sodium cyanide ortrimethylsilyl cyanide, and an acid such as hydrochloric orp-toluenesulfonic acid in alcohol or mixed aqueous alcohol solvent at25° C. to 50° C. to give the α-aminonitrile (1) Aminonitrile (1) is mostconveniently hydrolyzed by addition to concentrated sulfuric acid at 25°C. to 50° C. followed by aqueous workup and neutralization with base togive aminocaboxamide (2) Aminocarboxamide (2) may be cyclized by heatingwith 3 to 10 equivalents of triethyl orthoformate and 1 to 5 equivalentsof an organic acid such as formic acid or acetic acid at 100° C. to 150°C. Alternatively, aminocarboxamide (2) may be cyclized by heating withexcess formamide in the presence of a strong acid such as sulfuric acidto provide 1,3,8-triazaspiro[4.5]dec-2-en-4-one (3).1,3,8-Triazaspiro[4.5]dec-2-en-4-one (3) may be reduced with sodiumborohydride in an alcohol solvent such as ethanol at 25° C. to 50° C. toprovide N-benzyl protected 1,3,8-triazaspiro[4.5]decan-4-one (4). Thepiperidine nitrogen may be deprotected by hydrogenation in the presenceof a metal catalyst such as palladium in ethyl acetate or alcoholsolvent to provide (5). Alternatively,1,3,8-triazaspiro[4.5]dec-2-en-4-one (3) may be directly converted tothe debenzylated 1,3,8-triazaspiro[4.5]decan-4-one (5) by hydrogenationat 60 psi in the presence of a metal catalyst such as palladium and anacid catalyst such as hydrochloric acid in ethanol.1,3,8-Triazaspiro[4.5]decan-4-one (5) may be converted to carbamate (6)using benzyl chloroformate and pyridine in dichloromethane. The N₃substituent may be introduced by reaction of carbamate (6) with asuitably protected haloalkyl(aryl) ester (for example, PG=methyl ort-butyl) in the presence of a base such as potassium carbonate orlithium bis(trimethylsilylamide) in a polar aprotic solvent such asN,N-dimethylformamide at 25° C. to 50° C. to provide (7). Alternatively,in situations where the N₃ substituent is a phenyl or aryl ester groupit may be necessary to use Buchwald's protocol. In these cases,carbamate (6) may be reacted with an alkyl iodobenzoate in the presenceof copper iodide, dimethylethylenediamine, and potassium carbonate inacetonitrile at 75° C. to provide (7). Carbamate (7) may be deprotectedvia hydrogenation at atmospheric pressure in the presence of a metalcatalyst such as palladium in ethyl acetate or alcohol solvent toprovide deprotected 1,3,8-triazaspiro[4.5]decan-4-one (8). The N₈substituent may be introduced by reaction of (8) with the appropriate(hetero)aryl alkyl halide or tosylate in the presence of a base such aspotassium carbonate, and 0.1-1 equivalent of sodium iodide catalyst in asuitable solvent such as acetone or 2-butanone at 50° C. to 80° C. toprovide fully substituted 1,3,8-triazaspiro[4.5]decan-4-one (9). If theester protective group in (9) is a t-butyl group it may be removed bytreatment with a strong acid such as hydrochloric acid in dioxane or20-50% trifluoroacetic acid in dichloroethane to provide carboxylic acid(10) as a trifluoroacetic acid salt. If the ester protective group in(9) is a methyl or ethyl group it may be removed by treatment withlithium hydroxide in aqueous methanol followed by careful neutralizationwith acetic acid to provide carboxylic acid (10). Specific examples ofthis generic description are found in this application herein.

DEFINITIONS

As described herein, R₁, R₂ and R₃ substituents on the1,3,8-triazaspiro[4.5]decan-4-one core structure are described by theirsystematic chemical names. For purposes of this application, the R₁ issubstituted at the 8 position of the 1,3,8-triazaspiro[4.5]decan-4-onecore structure, R₂ is substituted at the 1 position, and R₃ substituentsare at the 3 position. For example, one R₁ substitution described hereinis 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl. The chemicalstructure defined by that systematic name is as follows:

The described moiety connects to the core via the propyl group, thus thecore plus 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl for R₁yields the following:

R₂ and R₃ substitutions are described in the same manner. An R₂substituent described herein is 4-fluorophenyl. According to standardchemical naming conventions, and as one of ordinary skill in the artwould readily know, for the fluoro atom to attach at the 4-position ofthe phenyl ring, by definition the phenyl attaches at R₂ para to thefluoro:

An R₃ described herein is:

Combined with the structure above, the following compound is described:

The term “C₁-C₆alkyl” refers to straight or branched hydrocarbon chains.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, pentan-2-yl,pentan-3-yl, isopentyl, neopentyl, hexyl, hexan-2-yl, hexan-3-yl,4-methylpentyl, 3,3-dimethylbutyl, 4,4-dimethylpental-2-yl,2-methylpentan-3-yl, 4-methylpentan-2-yl, 2-methylpentyl,3-methylpentyl, 2,3-dimethylbutyl, and the like. The term “C₁-C₆alkyl”is considered herein to be equivalent to term written with a spacebetween the “C₁-C₆” and the “alkyl” (“C₁-C₆ alkyl”). In one aspect ofthe invention the alkyl linking group at the R₁ position is C₂-C₄alkyl,that is, ethyl, propyl or butyl.

The term “cycloalkyl” refers to a non-aromatic carbocyclic ring or ringsystem, which may be saturated (i.e., a “cycloalkyl”), or unsaturated(i.e., a “cycloalkenyl”), generally the former. Cycloalkyl groups mayhave a simple single ring system or a more complex multi-ring fused orbridged system. Preferred cycloalkyl groups have from 3 to 7 members.More preferred cycloalkyl groups have 5 or 6 members. Examples ofcycloalkyl groups include, for example, cyclohexyl, cyclopentyl,cyclobutyl, cyclopropyl and cycloheptyl. Examples of more complexcycloalkyl groups include the following: Examples of more complexcycloalkyl groups include the following: bicyclo[4.1.0]hept-2-yl-,bicyclo[4.1.0]hept-3-yl-, bicyclo[4.1.0]hept-1-yl-,bicyclo[3.1.0]hex-6-yl-, adamantyl-1-yl-, adamantyl-2-yl-,octahydro-pentalen-2-yl-, endo-bicyclo[2.2.1]hept-2-yl-,exo-bicyclo[2.2.1]hept-2-yl-, endo-bicyclo[2.2.2]oct-2-yl-, andexo-bicyclo[2.2.2]oct-2-yl-.

The term “halo” and “halogen” refer to one or more —F, —Cl, —Br and —I.

The term “optionally substituted” refers to the presence or absence ofone or more substitutions, as set forth herein.

As used herein, the term “pharmaceutically acceptable salts” or “apharmaceutically acceptable salt thereof” refer to organic and inorganicacids that include, but not limited to, acetic, acrolate, ascorbic,benzenesulfonic (besylate), benzoic, bicarbonic, bisulfate, bisulfic,bitartaric, camphorsulfonic, carbonic, citric, edetic, ethanedisulfonic, ethenesulfonic, formic, fumaric, glucoheptonic, gluconic,glucuronic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,dydrabamic, hydrobromic, hydrochloric, hydroiodide, isethionic, lactic,lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic,mucic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, phthalic, propionic, pyrosulfate,salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic,sulfuric, tannic, tartaric, p-toluenesulfonic, and the like. The termsalso refer to the group including, but not limited to, alkali metalssuch as sodium, potassium, and lithium; alkaline earth metals such ascalcium and magnesium; other metals, such as aluminum, zinc; ammonia andorganic amines, such as mono-, di- or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis, or tris-(2-hydroxy-lower alkyl amines, suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethylamine;N-methyl-D-glucamine; amino acids such as arginine, lysine, and thelike, and zwitterions, such as glycine and the like.

Furthermore, the term “salt” as used herein also includes coordinationcomplexes between ionic compounds of the invention and one or morecounterions.

There are numerous substituents that may be chosen as R₁ substituents.Here are generic names and specific formulas that are used to explifythe names.

-   (2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)(C₁-C₄alkyl) optionally    substituted at the 3 position with cyclopropyl or at the 6 position    with chlorine (the latter shown),

-   (2-oxobenzo[d]oxazol-3(2H)-yl)(C₁-C₄alkyl) propyl shown,

-   (2-oxobenzo[d]thiazol-3(2H)-yl)(C₁-C₆alkyl) propyl shown,

-   (2-oxoindolin-1-yl)(C₁-C₆alkyl) optionally substituted at the    3-position with one or two components chosen from methyl or fluoro    propyl link with 3-methyl, 3-flours shown,

-   (3-spirocyclopropane-(2-oxoindolin-1-yl))(C₁-C₆alkyl),

-   (2-oxoindolin-3-yl))(C₁-C₆alkyl),

-   phenyl(C₁-C₆alkyl),

-   1-hydroxy-1-phenylmethyl(C₂-C₆ alkyl),

-   1-acetoxy-1-phenylmethyl(C₂-C₆ alkyl),

-   bis(4-fluorophenyl)methyl-(C₁-C₆alkyl),

-   (1H-benzo[d][1,2,3]triazol-1-yl)(C₂-C₆alkyl),

-   1-phenyl-1-oxo-(C₂-C₆alkyl) optionally substituted at the 4 position    of the phenyl with halo,

-   2,3-dihydrobenzo[b][1,4]dioxine-2-(C₁-C₆alkyl),

-   1-(thiophen-2-yl)-1-oxo-(C₁-C₆alkyl),

-   3-oxo-2H-benzo[b][1,4]oxazin-4-yl))(C₁-C₆alkyl),

-   ((3-(C₁-C₆alkyl)oxycarbonyl(C₁-C₆alkyl))-1H-indol-1-yl)(C₁-C₆alkyl)

-   (2-(C₁-C₆alkyl)oxycarbonyl-1H-indol-1-yl)(C₁-C₆alkyl)

Example 1 Compound Affinity

Affinity for the dopamine D2 receptor was tested in vitro, and thefollowing describes the construction of cell lines expressing human D2receptor, as well as the binding assays themselves.

Establishment of Stable Cell Lines Expressing Either the Cloned HumanD_(2S) Receptor or the Cloned Human D_(2L) Receptor.

The human D₂ receptor exists in two isoforms: the short form (D_(2S))and the long form (D_(2L)). The two isoforms are generated from the D₂gene by alternative splicing and the D_(2L) isoform differs from theD_(2S) isoform by the addition of 29 amino acids in the thirdintracellular loop of its protein structure.

To establish HEK-293 cell lines stably expressing either the humanD_(2S) or the human D_(2L), the human dopamine D_(2S) receptor (GenebankAccession Number NM_(—)016574) and human dopamine D_(2L) receptor(Genebank Accession Number BC021195) were amplified by PCR from OrigenecDNA clones TC308892 and SC123573 (respectively) using the followingprimers: 5 CACCATGGATCCACTGAATCTGTCCTG-3 sense and 5GCAGCAGAGTCAGCAGTGGA-3 antisense. The resulting PCR products wererespectively cloned into pENTR-D-TOPO (Invitrogen), sequenced and thentransferred into the pcDNA3.2-DEST (Invitrogen) using the LR-clonasegateway reaction (Invitrogen) and sequenced again to verify the genessequence.

HEK293 cells were maintained in Eagles Minimum Essential Medium (MEM)supplemented with 0.292 g/L L-glutamine and 10% (v/v) fetal calf serumat 37° C. in a 5% CO₂ humidified atmosphere. Cells were grown to 60-80%confluency in 10 cm dishes before transfection. Transfection of theD_(2S) and D_(2L) containing pcDNA3.2-DEST into HEK-293 cells wereperformed using Lipofectamine 2000 (Invitrogen). Transfected cells wereseeded and diluted 2 days after transfection and maintained in culturemedium supplemented with 500 μg/mL G418. The HEK-293 cell lineexpressing the huD_(2S) (R2D_(2S)) and the huD_(2L) (R2D_(2L)) weremaintained in culture medium supplemented with 500 μg/mL G418.

D2 Receptor Binding Assays Cell Culture

HEK293 cells were in Eagles Minimum Essential Medium (MEM) supplementedwith 10% FBS, 0.292 g/liter L-glutamine, 10⁵ units/liter penicillin, 100mg/liter streptomycin and 500 mg/ml Geneticin at 37° C. in a 5% CO₂humidified atmosphere. Cells were grown to 80-90% confluence andharvested with cell stripper (Cellgro #25-056-CI). Cells were thenwashed with PBS (2×). Cells were either pelleted and frozen at −80° C.or membranes were prepared immediately.

Membrane Preparation

Cells from pellet were resuspended in homogenization buffer (15 mMTris*HCl, 2 mM MgCl₂*6H₂O, 0.3 mM EDTA, 1 mM EGTA pH 7.4 @ 4° C.). Cellswere then homogenized using a Polytron (PT 1200) homogenizer at setting6 for 10 seconds. Crude membranes were pelleted at 39, 412 g for 15 min,at 4° C. (2×) in a Sorval RC6 plus centrifuge. Membranes were finallyresuspended in resuspension buffer (50 mM Tris*HCl, 120 mM NaCl, 10 mMMgCl₂*6H₂O, 1 mM EDTA pH 7.4 @ 4° C.) and sonicated (Fisher SonicDismembrator) at setting 5 for 10 seconds.

Assay

The radioligand binding assays were conducted in microtiter plates(Costar #3961) with a final volume of 1.0 mL.

The membranes were thawed at room temperature, briefly homogenized usinga sonicator, diluted in assay buffer and kept on wet ice until beingadded to the assay plate. Membranes were diluted to a final targettissue concentration of 10 μg protein per well. The specific bindingshould be greater than 80% with less than 10% total radioligand bound tominimize ligand depletion errors.

First compound of the invention (50 μL) or assay buffer (50 mM Tris*HCl,120 mM NaCl, 5 mM MgCl₂*6H₂O, 1 mM EDTA, 5 mM KCl pH 7.4 @37° C. plus0.025% BSA), buffer (700 μL) and then membrane (200 μL) were added tothe deep well assay plate, which was then shaken for 10 minutes.Finally, radioligand (50 μL) was added.

The assay plates were incubated at 37° C. for 120 minutes.

The assay plate were filtered over 0.3% PEI pretreated glass fiberfiltermats (GF/C) using a Packard Filtermate cell harvester. The platewere then rinsed with ice cold wash buffer (1 mL/well; 50 mM Tris*HCl,0.9% NaCl pH 7.4 @ 4° C.) three times and then air dried.

For each compound of the invention tested, the concentration producing50% inhibition of binding (IC₅₀) was determined using the OneSiteCompetition equation, since the F-test did not yield significance whencompared with a Sigmoidal Dose-response curve with variable slope. Sincethe radioligand K_(D) is known (0.09 nM), the inhibition dissociationconstant (K_(i)) of each compound was determined according to the methodof Cheng & Prusoff (Cheng, Y-C and Prusoff (1973). Biochem Pharmacol.,22: 3099-3108).

Bound radioligand was determined by liquid scintillation counting. Todetermine radioligand concentration, three (3) aliquots of theradioligand solution were counted by liquid scintillation (10 uL diluted³H-ligand+40 uL Scin 20 into GF/C filter plate).

In the following tables, compound IC₅₀ values for D₂ are shown. IC₅₀values are reported on a scale of 1 through 5, wherein the value scaleis defined as follows:

Receptor Affinity Scale IC₅₀ value <10 nM 10-50 nM 51-200 nM 201-999nM >1 uM Scaled number 1 2 3 4 5 Affinity Compound Score 11 1 17 1 19 121 1 22 1 23 1 25 1 26 1 30 1 35 1 38 1 39 1 40 1 43 1 52 1 56 1 69 1 701 71 1 72 1 76 1 85 1 89 1 100 1 102 1 104 1 108 1 120 1 123 1 130 1 1371 138 1 143 1 145 1 146 1 148 1 149 1 152 1 153 1 154 1 155 1 156 1 1591 160 1 161 1 162 1 163 1 164 1 166 1 167 1 168 1 170 1 171 1 173 1 1741 175 1 176 1 177 1 179 1 180 1 182 1 186 1 187 1 188 1 189 1 190 1 1911 192 1 193 1 194 1 195 1 196 1 197 1 198 1 199 1 210 1 211 1 212 1 2131 214 1 215 1 216 1 217 1 218 1For Examples 2 through 112:

PTLC=preparative thin layer chromatography

Reported HPLC retention times (rt=min) chromatography conditions:Phenomenex 150×4.6 mm, 5μ; Gradient 20 mM ammonium acetate buffer, pH5.7: acetonitrile=85:15 for 2 min, up to 10:90 in 18 min, stay at 10:90for 3 min and back to 85:15 in 2 min. 30 min run, monitor at 254 nm,flow rate 1 mL/min, injection 20 μL

Example 2 Compound 6 Methyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.19 g, 0.4 mmol) was added 4M solution of HCl in dioxane (2 mL). Afterstirring at room temperature for 3 hours, the reaction mixture wasconcentrated in vacuo to obtain methyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.138g, 1.0 mmol) in N,N-dimethylformamide (4 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.121 g, 0.4 mmol).After stirring at 55° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated by pTLC(10% methanol/dichloromethane) to obtain the product (0.09 g, 41%); ¹HNMR (DMSO-d₆): δ 1.61 (br, 2H), 1.83 (br, 2H), 2.32-2.34 (m, 2H),2.50-2.53 (m, 2H), 2.64-2.66 (m, 6H), 3.85 (s, 3H), 4.58-4.62 (m, 4H)6.88-6.97 (m, 4H), 7.21-7.23 (m, 4H), 7.51-7.57 (m, 3H), 7.89 (d, 2H,J=7.2 Hz), 10.80 (s, 1H); MS for C₃₂H₃₅N₅O₄ m/z 554.12 (M+H)⁺.

tert-Butyl3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.15 g, 0.45mmol) and potassium carbonate (0.124 g, 0.9 mmol) inN,N-dimethylformamide (4 mL), was added methyl 3-(bromomethyl)benzoate(0.114 g, 0.5 mmol). After stirring at 60° C. for 60 hours, the reactionmixture was diluted with ethyl acetate (25 mL), washed with dilutecitric acid, water and brine. The organic phase was dried over MgSO₄,filtered and concentrated to a yellowish brown solid (0.2 g, 93%); ¹HNMR (DMSO-d₆): δ 1.45 (s, 9H), 1.64 (d, 2H, J=13.6 Hz), 2.41-2.49 (m,2H), 3.48 (br, 2H), 3.85 (s, 3H), 3.86-3.90 (m, 2H), 4.59-4.64 (m, 4H),6.68 (d, 2H, J=8.4 Hz), 6.77 (t, 1H, J=7.4 Hz), 7.17 (t, 2H, J=8 Hz),7.54-7.60 (m, 2H), 7.89-7.92 (m, 2H); MS for C₂₇H₃₃N₃O₅ m/z 480.08(M+H)⁺.

tert-Butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (0.75 g,3.24 mmol) in dichloromethane (25 mL) and N,N-diisopropylethylenediamine(1.13 mL, 6.48 mmol, d=0.742), was added di-tert-butyl dicarbonate (0.71g, 3.27 mmol). After stirring at room temperature for 18 hours, thereaction mixture was diluted with dichloromethane (100 mL), washed withdilute citric acid, water and brine. The organic phase was dried overMgSO₄, filtered and concentrated to cream solid (1.1 g, 99%); ¹H NMR(DMSO-d₆): δ 1.45 (s, 9H), 1.58 (d, 2H, J=14 Hz), 2.36-2.39 (m, 2H),3.39 (br, 2H), 3.84 (br, 2H), 4.59 (s, 2H), 6.68 (d, 2H, J=8 Hz), 6.75(t, 1H, J=7.2 Hz), 7.18 (t, 2H, J=8.2 Hz), 8.77 (s, 1H); MS forC₁₈H₂₅N₃O₃ m/z 332.04 (M+H)⁺.

Example 3 Compound 7 Methyl5-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)pentanoate

To tert-butyl3-(5-methoxy-5-oxopentyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.09 g, 0.2 mmol) was added 4M solution of HCl in dioxane (1 mL). Afterstirring at room temperature for 2 hours, the reaction mixture wasconcentrated in vacuo to obtain methyl5-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)pentanoate as ahydrochloride salt. To a solution of the hydrochloride salt andpotassium carbonate (0.069 g, 0.5 mmol) in N,N-dimethylformamide (2 mL),was added 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.06 g,0.2 mmol). After stirring at 55° C. for 18 hours, the reaction mixturewas diluted with ethyl acetate (25 mL), washed with water and brine. Theorganic phase was dried over MgSO₄, filtered, concentrated and isolatedby pTLC (10% methanol/dichloromethane) to obtain the product (0.05 g,48%); ¹H NMR (DMSO-d₆): δ 1.50-1.57 (m, 6H), 1.81 (br, 2H), 2.32-2.36(m, 4H), 2.60-2.67 (m, 8H), 3.57 (s, 3H), 3.84 (t, 2H, J=6.8 Hz), 4.64(s, 2H), 6.77 (t, 1H, J=7.2 Hz), 6.88 (d, 2H, J=8 Hz), 6.96 (d, 3H,J=3.2 Hz), 7.17-7.19 (m, 1H), 7.25 (t, 2H, J=8.4 Hz), 10.8 (s, 1H); MSfor C₂₉H₃₇N₅O₄ m/z 520.11 (M+H)⁺.

tert-Butyl3-(5-methoxy-5-oxopentyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.15 g, 0.45mmol) and potassium carbonate (0.093 g, 0.68 mmol) inN,N-dimethylformamide (4 mL), was added methyl-5-bromovalerate (0.071mL, 0.5 mmol, d=1.374). After stirring at 60° C. for 60 hours, thereaction mixture was diluted with ethyl acetate (25 mL), washed withdilute citric acid, water and brine. The organic phase was dried overMgSO₄, filtered and isolated by pTLC (50% ethyl acetate/hexanes) to getthe title compound (0.1 g, 50%); ¹H NMR (DMSO-d₆): δ 1.43 (s, 9H),1.46-1.57 (m, 8H), 2.35 (t, 4H, J=7.6 Hz), 3.35 (t, 2H, J=6.8 Hz), 3.57(s, 3H), 3.85 (br, 2H), 4.67 (s, 2H), 6.71 (d, 2H, J=8 Hz), 6.71 (t, 1H,J=7.2 Hz), 7.20 (t, 2H, J=7.2 Hz); MS for C₂₄H₃₅N₃O₅ m/z 446.09 (M+H)⁺.

Example 4 Compound 8 Ethyl4-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)butanoate

To a solution of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.15 g, 0.45mmol) and potassium carbonate (0.124 g, 0.9 mmol) inN,N-dimethylformamide (4 mL), was added ethyl-4-bromobutyrate (0.072 mL,0.5 mmol, d=1.35). After stirring at 60° C. for 60 hours, the reactionmixture was diluted with ethyl acetate (25 mL), washed with dilutecitric acid, water and brine. The organic phase was dried over MgSO₄,filtered and concentrated in vacuo to obtain tert-butyl3-(4-ethoxy-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate.

To tert-butyl3-(4-ethoxy-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.09 g, 0.2 mmol) was added 4M solution of HCl in dioxane (2 mL). Afterstirring at room temperature for 2 hours, the reaction mixture wasconcentrated in vacuo to obtain ethyl4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)butanoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.124g, 0.9 mmol) in N,N-dimethylformamide (3 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.109 g, 0.36 mmol).After stirring at 60° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated by pTLC(10% methanol/dichloromethane) to obtain the product (0.085 g, 36%); ¹HNMR (DMSO-d₆): δ 1.16 (t, 3H, J=7.2 Hz), 1.52 (d, 2H, J=12.4 Hz),1.80-1.84 (m, 4H), 2.29-2.32 (m, 4H), 2.61-2.67 (m, 6H), 3.31-3.35 (m,2H), 3.84 (m, 2H), 4.03 (q, 2H, J=6.8 Hz), 4.65 (br, 2H), 6.76 (t, 1H,J=7.2 Hz), 6.88 (d, 2H, J=8 Hz), 6.96-7.07 (m, 3H), 7.14 (m, 1H), 7.25(t, 2H, J=8 Hz), 10.8 (s, 1H); MS for C₂₉H₃₇N₅O₄ m/z 520.15 (M+H)⁺.

Example 5 Compound 113-((4-Cho-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.86 g, 1.44 mmol) was added 4M solution of HCl in dioxane (10 mL).After stirring at room temperature for 4 hours, the reaction mixture wasconcentrated in vacuo and lyophilized in acetonitrile/water (1:1) toobtain the title compound as a hydrochloride salt (0.8 g); ¹H NMR(DMSO-d₆): δ 1.89 (d, 2H, J=14.4 Hz), 2.15 (t, 2H, J=6.4 Hz), 2.90-2.96(m, 2H), 3.19-3.22 (m, 2H), 3.50-3.66 (m, 6H), 3.90 (t, 2H, J=7.2 Hz),4.63-4.66 (m, 4H), 6.76 (t, 1H, J=7.2 Hz), 6.99-7.04 (m, 5H), 7.18-7.24(m, 3H), 7.50-7.57 (m, 2H), 10.77 (br, 1H), 10.91 (s, 1H), 13.01 (br,1H); MS for C₃₁H₃₃N₅O₄ m/z 540.07 (M+H)⁺.

tert-Butyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of benzyl3-(3-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(1.7 g, 3.06 mmol) in methanol (20 mL), was added 10 wt % palladium oncarbon (0.5 g). After stirring under hydrogen at room temperature andatmospheric pressure for 2 hours, the reaction mixture was filtered,washed with methanol, concentrated in vacuo to obtain tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (1.2g, 94%).

To a solution of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (1.2g, 2.84 mmol) and potassium carbonate (0.59 g, 4.3 mmol) inN,N-dimethylformamide (20 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.86 g, 2.84 mmol).After stirring at 55° C. for 5 hours, the reaction mixture was dilutedwith ethyl acetate (100 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated byBiotage flash chromatography (2-10% methanol/dichloromethane) to obtainthe title compound (1 g, 59%); ¹H NMR (DMSO-d₆): δ 1.51 (s, 9H), 1.60(d, 2H, J=13.2 Hz), 1.82 (t, 2H, J=6.4 Hz), 2.35 (t, 2H, J=6.4 Hz),2.53-2.60 (m, 4H), 2.65-2.71 (m, 4H), 3.85 (t, 2H, J=6.8 Hz), 4.56-4.60(m, 2H), 6.76 (t, 1H, J=14.4 Hz), 6.85 (d, 2H, J=8 Hz), 6.95-6.97 (m,3H), 7.17-7.24 (m, 3H), 7.48-7.54 (m, 2H), 7.78 (s, 1H), 7.82 (dt, 1H,J=7.2 and 1.6 Hz) 10.81 (s, 1H); MS for C₃₅H₄₁N₅O₄ m/z 596 (M+H)⁺.

Benzyl3-(3-tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of benzyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (3 g, 8.2mmol) and potassium carbonate (1.7 g, 12.3 mmol) inN,N-dimethylformamide (50 mL), was addedtert-butyl-3-(bromomethyl)benzoate (2.34 g, 8.62 mmol). After stirringat 55° C. for 18 hours, the reaction mixture was diluted with ethylacetate (200 mL), washed with dilute citric acid, water and brine. Theorganic phase was dried over MgSO₄, filtered, and isolated by Biotageflash chromatography (10-100% ethyl acetate/hexanes) to obtain the titlecompound (1.7 g, 37%); ¹H NMR (DMSO-d₆): δ 1.52 (s, 9H), 1.71 (d, 2H,J=13.6 Hz), 2.35-2.43 (m, 2H), 3.57 (br, 2H), 3.99-4.05 (m, 2H),4.61-4.63 (m, 4H), 5.10-5.16 (m, 2H), 6.71 (d, 2H, J=8.4 Hz), 6.78 (t,1H, J=7.2 Hz), 7.17 (t, 2H, J=7.6 Hz), 7.33-7.38 (m, 5H), 7.49-7.56 (m,2H), 7.80-7.84 (m, 2H); MS for C₃₃H₃₇N₃O₅ m/z 556.07 (M+H)⁺.

Benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (5 g, 21.6mmol) in dichloromethane (50 mL) and pyridine (3.5 mL, 43.2 mmol,d=0.978), was added benzyl chloroformate (3.15 mL, 22.04 mmol, d=1.195).After stirring at room temperature for 16 hours, the reaction mixturewas diluted with dichloromethane (100 mL), washed with dilute citricacid, water and brine. The organic phase was dried over MgSO₄, filteredand concentrated to cream solid (6 g, 76%); ¹H NMR (DMSO-d₆): δ 1.65 (d,2H, J=13.6 Hz), 2.32-2.40 (m, 2H), 3.51 (br, 2H), 3.95-3.99 (m, 2H),4.59 (s, 2H), 5.11-5.15 (m, 2H), 6.68 (d, 2H, J=8 Hz), 6.75 (t, 1H,J=7.2 Hz), 7.18 (t, 2H, J=7.6 Hz), 7.30-7.38 (m, 5H), 8.81 (s, 1H); MSfor C₂₁H₂₃N₃O₃ m/z 366 (M+H)⁺.

Example 6 Compound 13 Methyl5-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-5-phenylpentanoate

To a solution of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.2 g, 0.6mmol) and potassium carbonate (0.124 g, 0.9 mmol) inN,N-dimethylformamide (3 mL), was added methyl5-bromo-5-phenylpentanoate (0.163 g, 0.6 mmol). After stirring at 60° C.for 18 hours, the reaction mixture was diluted with ethyl acetate (25mL), washed with dilute citric acid, water and brine. The organic phasewas dried over MgSO₄, filtered and concentrated in vacuo to obtain thetitle compound.

To tert-butyl3-(5-methoxy-5-oxo-1-phenylpentyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.07 g, 0.13 mmol) was added 4M solution of HCl in dioxane (1.5 mL).After stirring at room temperature for 90 minutes, the reaction mixturewas concentrated in vacuo to obtain methyl5-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-5-phenylpentanoateas a hydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.045g, 0.32 mmol) in N,N-dimethylformamide (2 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.041 g, 0.13 mmol).After stirring at 60° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (20 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain the titlecompound (0.019 g, 25%); ¹H NMR (DMSO-d₆): δ 1.41-1.57 (m, 4H), 1.80 (t,2H, J=6.4 Hz), 1.98-2.10 (m, 2H), 2.33-2.49 (m, 7H), 2.64-2.70 (m, 4H),3.56 (s, 3H), 3.84 (t, 2H, J=6.8 Hz), 4.26 (d, 1H, J=5.2 Hz), 4.72 (d,1H, J=5.2 Hz), 5.15-5.19 (m, 1H), 6.76 (t, 1H, J=7.2 Hz), 6.86 (d, 2H,J=8.4 Hz), 6.96 (d, 3H, J=3.2 Hz), 7.17-7.24 (m, 3H), 7.29-7.32 (m, 1H),7.35-7.40 (m, 3H), 10.80 (s, 1H); MS for C₃₅H₄₁N₅O₄ m/z 596.06 (M+H)⁺.

Example 7 Compound 14 Methyl2-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(2-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.12 g, 0.25 mmol) was added 4M solution of HCl in dioxane (2.5 mL).After stirring at room temperature for 90 minutes, the reaction mixturewas concentrated in vacuo to obtain methyl2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.086g, 0.625 mmol) in N,N-dimethylformamide (2 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.076 g, 0.25 mmol).After stirring at 60° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain the titlecompound (0.04 g, 29%); ¹H NMR (DMSO-d₆): δ 1.64 (d, 2H, J=12.8 Hz),1.82 (t, 2H, J=6.8 Hz), 2.32 (t, 2H, J=6.4 Hz), 2.52-2.72 (m, 6H),3.83-3.85 (m, 5H), 4.59 (s, 2H), 5.86 (s, 2H), 6.76 (t, 1H, J=7.6 Hz),6.83 (d, 2H, J=8 Hz), 6.97 (d, 3H, J=2.8 Hz), 7.18-7.25 (m, 3H), 7.31(d, 1H, J=7.2 Hz), 7.44 (t, 1H, J=7.6 Hz), 7.61 (dt, 1H, J=7.2 and 1.2Hz), 7.89 (dd, 1H, J=8 and 1.6 Hz), 10.82 (s, 1H); MS for C₃₂H₃₅N₅O₄ m/z554.05 (M+H)⁺.

tert-Butyl3-(2-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.5 g, 1.5mmol) and potassium carbonate (0.41 g, 3.0 mmol) inN,N-dimethylformamide (3 mL), was added methyl 2-(bromomethyl)benzoate(0.38 g, 1.66 mmol). After stirring at 55° C. for 18 hours, the reactionmixture was diluted with ethyl acetate (25 mL), washed with dilutecitric acid, water and brine. The organic phase was dried over MgSO₄,filtered and isolated by Biotage flash chromatography (10-60% ethylacetate/hexanes) to obtain the title compound (0.12 g, 17%); ¹H NMR(DMSO-d₆): δ 1.46 (s, 9H), 1.70 (d, 2H, J=14 Hz), 2.41-2.49 (m, 2H),3.49-3.53 (m, 2H), 3.83-3.87 (m, 5H), 4.63 (s, 2H), 4.89 (s, 4H), 6.67(d, 2H, J=8.4 Hz), 6.77 (t, 1H, J=7.4 Hz), 7.18 (t, 2H, J=8.4 Hz), 7.34(d, 1H, J=8 Hz), 7.46 (d, 1H, J=7.6 Hz), 7.59-7.63 (m, 2H), 7.68 (dt,1H, J=7.6 and 0.8 Hz), 7.78 (t, 1H, J=6.8 Hz), 7.85 (d, 1H, J=7.6 Hz),7.91 (dd, 1H, J=7.6 and 1.6 Hz); MS for C₂₇H₃₃N₃O₅ m/z 480.04 (M+H)⁺.

Example 8 Compound 15 Methyl4-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(4-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.31 g, 0.65 mmol) was added 4M solution of HCl in dioxane (3 mL).After stirring at room temperature for 90 minutes, the reaction mixturewas concentrated in vacuo to obtain methyl4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.225g, 1.625 mmol) in N,N-dimethylformamide (3 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.196 g, 0.65 mmol).After stirring at 60° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain the titlecompound (0.11 g, 31%); ¹H NMR (DMSO-d₆): δ 1.61 (d, 2H, J=12.8 Hz),1.82 (t, 2H, J=6.8 Hz), 2.34 (t, 2H, J=6.4 Hz), 2.50-2.72 (m, 6H),3.83-3.87 (m, 5H), 4.54-4.61 (m, 4H), 6.76 (t, 1H, J=7.2 Hz), 6.84 (d,2H, J=8 Hz), 6.96 (d, 3H, J=3.2 Hz), 7.17-7.24 (m, 3H), 7.42 (d, 2H, J=8Hz), 7.96 (d, 2H, J=8.4 Hz), 10.82 (s, 1H); MS for C₃₂H₃₅N₅O₄ m/z 554.05(M+H)⁺.

tert-Butyl3-(4-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.75 g, 2.26mmol) and potassium carbonate (0.62 g, 4.52 mmol) inN,N-dimethylformamide (10 mL), was added methyl 4-(bromomethyl)benzoate(0.52 g, 2.26 mmol). After stirring at 60° C. for 18 hours, the reactionmixture was diluted with ethyl acetate (25 mL), washed with dilutecitric acid, water and brine. The organic phase was dried over MgSO₄,filtered and isolated by Biotage flash chromatography (10-60% ethylacetate/hexanes) to obtain the title compound (0.31 g, 29%); ¹H NMR(DMSO-d₆): δ 1.46 (s, 9H), 1.66 (d, 2H, J=14.4 Hz), 2.41-2.49 (m, 2H),3.83-3.85 (m, 7H), 4.56-4.64 (m, 4H), 6.68 (d, 2H, J=8 Hz), 6.77 (t, 1H,J=7.6 Hz), 7.17 (t, 2H, J=8.4 Hz), 7.44 (dd, 2H, J=8.8 and 2 Hz), 7.96(dd, 2H, J=8 and 3.2 Hz); MS for C₂₇H₃₃N₃O₅ m/z 480.04 (M+H)⁺.

Example 9 Compound 16 2-(Dimethylamino)ethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-((2-(dimethylamino)ethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.17 g, 0.32 mmol) was added 4M solution of HCl in dioxane (3 mL).After stirring at room temperature for 90 minutes, the reaction mixturewas concentrated in vacuo to obtain 2-(dimethylamino)ethyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.111g, 0.8 mmol) in N,N-dimethylformamide (2 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.097 g, 0.32 mmol).After stirring at 55° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (15% methanol/dichloromethane followed by 10%methanol/dichloromethane) to obtain the product (0.033 g, 17%); ¹H NMR(DMSO-d₆): δ 1.60 (d, 2H, J=12.4 Hz), 1.83 (t, 2H, J=6.4 Hz), 2.17 (s,6H), 2.32-2.34 (m, 2H), 2.59 (t, 2H, J=5.6 Hz), 2.67-2.72 (m, 6H), 3.85(t, 2H, J=6.4 Hz), 4.33 (t, 2H, J=5.6 Hz) 4.58-4.62 (m, 4H), 6.76 (t,1H, J=7.6 Hz), 6.84 (d, 2H, J=8 Hz), 6.96 (d, 3H, J=3.6 Hz), 7.18-7.24(m, 3H), 7.52-7.58 (m, 2H), 7.85-7.89 (m, 2H), 10.82 (s, 1H); MS forC₃₅H₄₂N₆O₄ m/z 611.10 (M+H)⁺.

tert-Butyl3-(3-((2-(dimethylamino)ethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of tert-Butyl3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(2 g, 4.17 mmol) in methanol (28 mL) was added lithium hydroxidemonohydrate (0.35 g, 8.34 mmol) in water (14 mL). After stirring at roomtemperature for 18 h, the reaction mixture was concentrated in vacuo,acidified with dilute citric acid, extracted with dichloromethane. Theorganic extracts were washed with brine, dried over MgSO₄, filtered andconcentrated to obtain3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid (1.88 g, 97%).

To a solution of3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid (0.34 g, 0.73 mmol), dicyclohexylcarbodiimide (0.18 g, 0.88 mmol)and 4-(dimethylamino)pyridine (0.011 g, 0.088 mmol) in dichloromethane(10 mL), was added N,N-dimethylethanolamine (0.065 mg, 0.73 mmol). Afterstirring at room temperature for 60 hours, the reaction mixture wasfiltered, concentrated in vacuo and isolated by preparatory TLC (10%methanol/dichloromethane) to obtain tert-butyl3-(3-((2-(dimethylamino)ethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.17 g, 43%); MS for C₃₀H₄₀N₄O₅ m/z 537 (M+H)⁺.

Example 10 Compound 174-((4-Oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To a solution of methyl4-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.4 g, 0.72 mmol) in methanol (6 mL) was added lithium hydroxidemonohydrate (0.061 g, 1.44 mmol) in water (2 mL). After stirring at roomtemperature for 18 h, the reaction mixture was concentrated in vacuo andisolated by reverse phase HPLC to obtain the title compound as anacetate salt (0.05 g, 13%); ¹H NMR (DMSO-d₆): δ 1.60 (d, 2H, J=6.8 Hz),1.82 (t, 2H, J=6.8 Hz), 2.35 (t, 2H, J=6.8 Hz), 2.50-2.71 (m, 7H), 3.85(t, 2H, J=6.8 Hz), 4.55-4.56 (m, 4H), 6.75 (t, 1H, J=7.2 Hz), 6.84 (d,2H, J=8.4 Hz), 6.96 (d, 3H, J=2.4 Hz), 7.17-7.26 (m, 5H), 7.85 (d, 2H,J=8 Hz); MS for C₃₁H₃₃N₅O₄ m/z 540.05 (M+H)⁺.

Example 11 Compound 18 (S)-sec-Butyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To (S)-tert-butyl3-(3-(sec-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.072 g, 0.14 mmol) was added 4M solution of HCl in dioxane (1.5 mL).After stirring at room temperature for an hour, the reaction mixture wasconcentrated in vacuo to obtain (S)-sec-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.048g, 0.35 mmol) in N,N-dimethylformamide (2 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.042 g, 0.14 mmol).After stirring at 55° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain the product(0.028 g, 34%); ¹H NMR (DMSO-d₆): δ 0.87 (t, 3H, J=7.2 Hz), 1.25 (d, 3H,J=6.4 Hz), 1.59-1.64 (m, 4H), 1.83 (br, 2H), 2.35 (br, 2H), 2.50-2.72(m, 6H), 3.86 (br, 2H), 4.59-4.62 (m, 4H), 4.94-4.99 (m, 1H), 6.67 (d,2H, J=8.4 Hz), 6.86 (t, 1H, J=7.2 Hz), 6.97 (s, 3H), 7.19-7.25 (m, 3H),7.51-7.56 (m, 2H), 7.85-7.89 (m, 2H), 10.82 (s, 1H); MS for C₃₅H₄₁N₅O₄m/z 596.13 (M+H)⁺.

(S)-tert-Butyl3-(3-(sec-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid (0.1 g, 0.22 mmol), dicyclohexylcarbodiimide (0.055 g, 0.22 mmol)and 4-(dimethylamino)pyridine (0.003 g, 0.026 mmol) in dichloromethane(5 mL), was added (S)-2-butanol (0.020 mL, 0.22 mmol, d=0.803). Afterstirring at room temperature for 60 hours, the reaction mixture wasfiltered, concentrated in vacuo and isolated by preparatory TLC (50%ethyl acetate/hexanes) to obtain the title compound (0.076 g, 66%); ¹HNMR (DMSO-d₆): δ 0.89 (t, 3H, J=7.2 Hz), 1.26 (d, 3H, J=6.4 Hz), 1.45(s, 9H), 1.60-1.66 (m, 4H), 2.32-2.45 (m, 2H), 3.45 (br, 2H), 3.89 (br,2H), 4.62-4.64 (m, 4H), 4.95-5.00 (m, 1H), 6.68 (d, 2H, J=8.4 Hz), 6.77(t, 1H, J=7.2 Hz), 7.17 (t, 2H, J=7.2 Hz), 7.51-7.59 (m, 2H), 7.86-7.92(m, 2H); MS for C₃₀H₃₉N₃O₅ m/z 544.05 (M+Na)⁺.

Example 12 Compound 192-((4-Oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To a solution of methyl2-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.27 g, 0.49 mmol) in methanol (3 mL) was added lithium hydroxidemonohydrate (0.041 g, 0.98 mmol) in water (1 mL). After stirring at roomtemperature for 18 h, the reaction mixture was concentrated in vacuo andisolated by reverse phase HPLC to obtain the title compound as anacetate salt (0.124 g, 47%); ¹H NMR (DMSO-d₆): δ 1.68 (d, 2H, J=13.2Hz), 1.85 (t, 2H, J=6.8 Hz), 2.42 (t, 2H, J=6.8 Hz), 2.59-2.65 (m, 2H),2.71-2.75 (m, 4H), 3.85 (t, 2H, J=6.8 Hz), 4.61 (s, 2H), 4.90 (s, 2H),6.74 (t, 1H, J=7.2 Hz), 6.83 (d, 2H, J=8.8 Hz), 6.96 (d, 3H, J=3.6 Hz),7.18-7.26 (m, 4H), 7.39 (t, 1H, J=8 Hz), 7.55 (t, 1H, J=6.8 Hz), 7.89(dd, 1H, J=8 and 1.2 Hz), 10.83 (s, 1H), 12.60 (br, 1H); MS forC₃₁H₃₃N₅O₄ m/z 540.01 (M+H)⁺.

Example 13 Compound 20 1-Methylpiperidin-4-yl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-((1-methylpiperidin-4-yloxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.01 g, 0.18 mmol) was added 4M solution of HCl in dioxane (2 mL).After stirring at room temperature for 2 hours, the reaction mixture wasconcentrated in vacuo to obtain 1-methylpiperidin-4-yl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.062g, 0.45 mmol) in N,N-dimethylformamide (1 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.054 g, 0.18 mmol).After stirring at 55° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain the product(0.03 g, 26%); ¹H NMR (DMSO-d₆): δ1.59-1.70 (m, 4H), 1.83-1.87 (m, 4H),2.15-2.35 (m, 7H), 2.50-2.72 (m, 8H), 3.85 (t, 2H, J=6.4 Hz), 4.59-4.62(m, 4H), 4.90-4.94 (m, 1H), 6.76 (t, 1H, J=7.6 Hz), 6.84 (d, 2H, J=8.4Hz), 6.96 (d, 3H, J=3.6 Hz), 7.18-7.24 (m, 3H), 7.51-7.58 (m, 2H), 7.85(s, 1H), 7.89 (d, 1H, J=7.2 Hz), 10.82 (s, 1H); MS for C₃₇H₄₄N₆O₄ m/z637.22 (M+H)⁺.

tert-Butyl3-(3-((1-methylpiperidin-4-yloxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid (0.15 g, 0.32 mmol), dicyclohexylcarbodiimide (0.079 g, 0.38 mmol)and 4-(dimethylamino)pyridine (0.005 g, 0.038 mmol) in dichloromethane(5 mL), was added (S)-2-butanol (0.037 g, 0.32 mmol). After stirring atroom temperature for 60 hours, the reaction mixture was filtered,concentrated in vacuo and isolated by preparatory TLC (10%methanol/dichloromethane) to obtain the title compound (0.1 g, 56%); ¹HNMR (DMSO-d₆): δ 1.45 (s, 9H), 1.63-1.66 (m, 4H), 1.89 (br, 2H),2.15-2.23 (m, 5H), 2.43-2.48 (m, 4H), 3.43 (br, 2H), 3.89 (br, 2H),4.60-4.65 (m, 4H), 4.95-5.00 (m, 1H), 6.67 (d, 2H, J=8.4 Hz), 6.76 (t,1H, J=7.6 Hz), 7.17 (t, 2H, J=8.4 Hz), 7.52-7.60 (m, 2H), 7.86-7.91 (m,2H); MS for C₃₂H₄₂N₄O₅ m/z 563.06 (M+H)⁺.

Example 14 Compound 21 Benzyl6-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)hexanoate

To tert-butyl3-(6-(benzyloxy)-6-oxohexyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.08 g, 0.15 mmol) was added 4M solution of HCl in dioxane (1.5 mL).After stirring at room temperature for 2 hours, the reaction mixture wasconcentrated in vacuo to obtain benzyl6-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)hexanoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.052g, 0.38 mmol) in N,N-dimethylformamide (1.5 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.045 g, 0.15 mmol).After stirring at 55° C. for 24 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain the titlecompound (0.026 g, 28%); ¹H NMR (DMSO-d₆): δ 1.23-1.29 (m, 2H),1.49-1.60 (m, 7H), 1.80 (t, 2H, J=6.4 Hz), 2.31-2.37 (m, 4H), 2.54-2.66(m, 6H), 3.30 (t, 2H, J=7.2 Hz), 3.84 (t, 2H, J=6.4 Hz), 4.63 (s, 2H),5.05 (s, 2H), 6.76 (t, 1H, J=7.2 Hz), 6.87 (d, 2H, J=8.4 Hz), 6.96 (d,3H, J=3.2 Hz), 7.12-7.18 (m, 1H), 7.25 (t, 2H, J=8.4 Hz), 7.29-7.34 (m,5H), 10.82 (s, 1H); MS for C₃₆H₄₃N₅O₄ m/z 610.12 (M+H)⁺.

tert-Butyl3-(6-(benzyloxy)-6-oxohexyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.4 g, 1.2mmol) and potassium carbonate (0.25 g, 1.8 mmol) inN,N-dimethylformamide (5 mL), was added benzyl 6-bromohexanoate (0.34 g,1.2 mmol). After stirring at 55° C. for 18 hours, the reaction mixturewas diluted with ethyl acetate (25 mL), washed with dilute citric acid,water and brine. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to obtain the title compound (0.08 g, 12%); MS forC₃₁H₄₁N₃O₅ m/z 536.16 (M+H)⁺.

Example 15 Compound 226-(4-Oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)hexanoicacid

To a solution of benzyl6-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)hexanoate(0.25 g, 0.41 mmol) in 4:1 ratio of ethyl acetate/methanol (4 mL), wasadded 10 wt % palladium on carbon (0.1 g). After stirring under hydrogenat room temperature and atmospheric pressure for 2 hours, the reactionmixture was filtered, washed with 1% acetic acid in methanol,concentrated in vacuo and isolated by reverse phase HPLC to obtain thetitle compound (0.09 g, 42%); ¹H NMR (DMSO-d₆): δ 1.21-1.26 (m, 2H),1.47-1.57 (m, 6H), 1.77-1.82 (m, 2H), 2.18 (t, 2H, J=7.2 Hz), 2.32 (t,2H, J=6.4 Hz), 2.59-2.67 (m, 6H), 2.91 (d, 2H, J=11.2 Hz), 3.84 (t, 2H,J=6.4 Hz), 4.64 (s, 2H), 6.76 (t, 1H, J=7.2 Hz), 6.88 (d, 2H, J=8.4 Hz),6.96 (d, 3H, J=3.6 Hz), 7.18-7.20 (m, 1H), 7.24 (t, 2H, J=8.8 Hz), 10.82(s, 1H); MS for C₂₉H₃₇N₅O₄ m/z 520.08 (M+H)⁺.

Example 16 Compound 24 2-(Dimethylamino)-2-oxoethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-((2-(dimethylamino)-2-oxoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.26 g, 0.47 mmol) was added 4M solution of HCl in dioxane (5 mL).After stirring at room temperature for 2 hours, the reaction mixture wasconcentrated in vacuo to obtain 2-(dimethylamino)-2-oxoethyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.162g, 1.18 mmol) in N,N-dimethylformamide (5 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.142 g, 0.47 mmol).After stirring at 55° C. for 24 hours, the reaction mixture was dilutedwith ethyl acetate (40 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated by pTLC(10% methanol/dichloromethane) to obtain the title compound (0.140 g,48%); ¹H NMR (DMSO-d₆): δ 1.60 (d, 2H, J=14 Hz), 1.82 (t, 2H, J=7.2 Hz),2.31-2.34 (m, 2H), 2.50-2.71 (m, 6H), 2.82 (s, 3H), 2.96 (s, 3H), 3.85(t, 2H, J=7.2 Hz), 4.61 (d, 4H, J=14.8 Hz), 5.02 (s, 2H), 6.76 (t, 1H,J=7.2 Hz), 6.85 (d, 2H, J=7.6 Hz), 6.96 (d, 3H, J=3.2 Hz), 7.19-7.24 (m,3H), 7.80-7.83 (m, 2H), 7.89-7.92 (m, 2H), 10.81 (s, 1H); MS forC₃₅H₄₀N₆O₅ m/z 625.05 (M+H)⁺.

tert-Butyl3-(3-((2-(dimethylamino)-2-oxoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.25 g, 0.54mmol) and potassium carbonate (0.11 g, 0.81 mmol) inN,N-dimethylformamide (5 mL), was added 2-chloro-N,N-dimethylacetamide(0.055 mL, 0.54 mmol, d=1.182). After stirring at 65° C. for 18 hours,the reaction mixture was diluted with ethyl acetate (25 mL), washed withdilute citric acid, water and brine. The organic phase was dried overMgSO₄, filtered and purified by Biotage flash chromatography (1-15%methanol/dichloromethane) to obtain the title compound (0.27 g, 91%); ¹HNMR (DMSO-d₆): δ 1.45 (s, 9H), 1.65 (d, 2H, J=13.6 Hz), 2.41-2.48 (m,2H), 2.82 (s, 3H), 2.96 (s, 3H), 3.45 (br, 2H), 3.90 (br, 2H), 4.63-4.66(m, 4H), 5.03 (s, 2H), 6.68 (d, 2H, J=8 Hz), 6.76 (t, 1H, J=7.6 Hz),7.17 (t, 2H, J=8.8 Hz), 7.54-7.63 (m, 2H), 7.91-7.93 (m, 2H); MS forC₃₀H₃₈N₄O₆ m/z 551.04 (M+H)⁺.

Example 17 Compound 25 2-Morpholinoethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-((2-morpholinoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.22 g, 0.38 mmol) was added 4M solution of HCl in dioxane (4 mL).After stirring at room temperature for 2 hours, the reaction mixture wasconcentrated in vacuo to obtain 2-morpholino-2-oxoethyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.1312g, 0.95 mmol) in N,N-dimethylformamide (4 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.115 g, 0.38 mmol).After stirring at 55° C. for 60 hours, the reaction mixture was dilutedwith ethyl acetate (40 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (12% methanol/dichloromethane) to obtain the titlecompound (0.13 g, 52%); ¹H NMR (DMSO-d₆): δ 1.60 (d, 2H, J=12.4 Hz),1.82 (t, 2H, J=7.2 Hz), 2.32-2.42 (m, 6H), 2.57-2.72 (m, 8H), 3.51 (t,4H, J=4.4 Hz), 3.86 (br, 2H), 4.36 (t, 2H, J=5.6 Hz), 4.59-4.62 (m, 4H),6.76 (t, 1H, J=7.2 Hz), 6.85 (d, 2H, J=7.6 Hz), 6.97 (s, 3H), 7.18-7.25(m, 3H), 7.52-7.59 (m, 2H), 7.85-7.89 (m, 2H), 10.82 (s, 1H); MS forC₃₇H₄₄N₆O₅ m/z 653.09 (M+H)⁺.

tert-Butyl3-(3-((2-morpholinoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid (0.3 g, 0.65 mmol), dicyclohexylcarbodiimide (0.16 g, 0.78 mmol)and 4-(dimethylamino)pyridine (0.01 g, 0.078 mmol) in dichloromethane(10 mL), was added hydroxyethyl morpholine (0.037 g, 0.32 mmol,d=1.072). After stirring at room temperature for 18 hours, the reactionmixture was filtered, concentrated in vacuo and isolated by preparatoryTLC (5% methanol/dichloromethane) to obtain the title compound (0.22 g,59%); ¹H NMR (DMSO-d₆): δ 1.45 (s, 9H), 1.59-1.66 (m, 4H), 2.43-2.48 (m,4H), 2.66 (t, 2H, J=5.6 Hz), 3.32-3.51 (m, 4H), 3.89 (br, 2H), 3.90 (br,2H), 4.37 (t, 2H, J=5.6 Hz), 4.62-4.65 (m, 4H), 6.68 (d, 2H, J=8.4 Hz),6.77 (t, 1H, J=7.2 Hz), 7.17 (t, 2H, J=8.8 Hz), 7.53-7.61 (m, 2H),7.86-7.90 (m, 2H); MS for C₃₂H₄₂N₄O₆ m/z 579.09 (M+H)⁺.

Example 18 Compound 26 (R)-Quinuclidin-3-yl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a refluxing solution of methyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.33 g, 0.59 mmol) and (R)-3-quinuclidinol (0.3 g, 2.4 mmol) in toluene(5 mL), was added titanium(IV)-i-propoxide (0.173 mL, 0.59 mmol,d=0.97). After refluxing for 18 h, the reaction mixture was concentratedin vacuo and isolated by reverse phase HPLC to obtain the title compound(0.13 g, 34%); ¹H NMR (DMSO-d₆): δ 1.31-1.34 (m, 1H), 1.51-1.55 (m, 4H),1.78-1.88 (m, 3H), 1.98-2.01 (m, 1H), 2.33 (t, 2H, J=7.2 Hz), 2.52-2.72(m, 11H), 3.15-3.21 (m, 1H), 3.85 (t, 2H, J=6.8 Hz), 4.59-4.62 (m, 4H),4.90-4.92 (m, 1H), 6.76 (t, 1H, J=7.2 Hz), 6.84 (d, 2H, J=8.4 Hz), 6.96(d, 3H, J=2.4 Hz), 7.17-7.24 (m, 3H), 7.52-7.59 (m, 2H), 7.87-7.92 (m,2H), 10.80 (br, 1H); MS for C₃₈H₄₄N₆O₄ m/z 649.11 (M+H)⁺.

Example 19 Compound 30 2-(Diethylamino)-2-oxoethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-((2-(diethylamino)-2-oxoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.22 g, 0.38 mmol) was added 4M solution of HCl in dioxane (3 mL).After stirring at room temperature for 2 hours, the reaction mixture wasconcentrated in vacuo to obtain 2-(diethylamino)-2-oxoethyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.131g, 0.95 mmol) in N,N-dimethylformamide (3 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.115 g, 0.38 mmol).After stirring at 55° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain the titlecompound (0.070 g, 28%); ¹H NMR (DMSO-d₆): δ 1.00 (t, 3H, J=7.2 Hz),1.14 (t, 3H, J=7.6 Hz), 1.61 (d, 2H, J=12 Hz), 1.82 (t, 2H, J=6 Hz),2.34 (t, 2H, J=6.8 Hz), 2.54-2.71 (m, 6H), 3.22-3.31 (m, 4H), 3.85 (t,2H, J=6.8 Hz), 4.61 (d, 4H, J=15.2 Hz), 5.01 (s, 2H), 6.76 (t, 1H, J=7.6Hz), 6.85 (d, 2H, J=8 Hz), 6.96 (d, 3H, J=2.8 Hz), 7.12-7.24 (m, 3H),7.54-7.60 (m, 2H), 7.90-7.93 (m, 2H), 10.82 (s, 1H); MS for C₃₇H₄₄N₆O₅m/z 653.08 (M+H)⁺.

tert-Butyl3-(3-((2-(diethylamino)-2-oxoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.2 g, 0.43mmol) and potassium carbonate (0.089 g, 0.65 mmol) inN,N-dimethylformamide (4 mL), was added 2-chloro-N,N-diethylacetamide(0.059 g, 0.43 mmol, d=1.089). After stirring at 55° C. for 18 hours,the reaction mixture was diluted with ethyl acetate (25 mL), washed withdilute citric acid, water and brine. The organic phase was dried overMgSO₄, filtered and isolated by Biotage flash chromatography to obtainthe title compound (0.22 g, 88%); MS for C₃₂H₄₂N₄O₆ m/z 579.10 (M+H)⁺.

Example 20 Compound 31 2-Amino-2-oxoethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-((2-amino-2-oxoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.22 g, 0.42 mmol) was added 4M solution of HCl in dioxane (4 mL).After stirring at room temperature for 2 hours, the reaction mixture wasconcentrated in vacuo to obtain 2-amino-2-oxoethyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.145g, 1.05 mmol) in N,N-dimethylformamide (4 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.127 g, 0.42 mmol).After stirring at 55° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain the titlecompound (0.12 g, 48%); ¹H NMR (DMSO-d₆): δ 1.60 (d, 2H, J=12.8 Hz),1.82 (t, 2H, J=6.4 Hz), 2.34 (t, 2H, J=6.4 Hz), 2.54-2.72 (m, 6H), 3.85(t, 2H, J=6.8 Hz), 4.59-4.67 (m, 6H), 6.76 (t, 1H, J=7.2 Hz), 6.85 (d,2H, J=8 Hz), 6.96 (d, 3H, J=2.8 Hz), 7.18-7.24 (m, 3H), 7.30 (s, 1H),7.53-7.60 (m, 3H), 7.93-7.97 (m, 2H), 10.82 (s, 1H); MS for C₃₃H₃₆N₆O₅m/z 597.01 (M+H)⁺.

tert-Butyl3-(3-((2-amino-2-oxoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.2 g, 0.43mmol) and potassium carbonate (0.089 g, 0.65 mmol) inN,N-dimethylformamide (3 mL), was added chloroacetamide (0.04 g, 0.43mmol). After stirring at 65° C. for 18 hours, the reaction mixture wasdiluted with ethyl acetate (25 mL), washed with dilute citric acid,water and brine. The organic phase was dried over MgSO₄, filtered andisolated by Biotage flash chromatography (2-10%methanol/dichloromethane) to obtain the title compound (0.22 g, 98%); ¹HNMR (DMSO-d₆): δ 1.45 (s, 9H), 1.65 (d, 2H, J=13.2 Hz), 2.32-2.45 (m,2H), 3.50 (br, 2H), 3.88 (br, 2H), 4.62-4.66 (m, 6H), 6.68 (d, 2H, J=8Hz), 6.77 (t, 1H, J=7.6 Hz), 7.17 (t, 2H, J=8.4 Hz), 7.30 (s, 1H),7.54-7.62 (m, 3H), 7.95-7.98 (m, 2H); MS for C₂₈H₃₄N₄O₆ m/z 523.04(M+H)⁺.

Example 21 Compound 32 2-Oxo-2-(piperidin-1-yl)ethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-Butyl4-oxo-3-(3-((2-oxo-2-(piperidin-1-yl)ethoxy)carbonyl)benzyl)-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.17 g, 0.29 mmol) was added 4M solution of HCl in dioxane (3 mL).After stirring at room temperature for 2 hours, the reaction mixture wasconcentrated in vacuo to obtain 2-oxo-2-(piperidin-1-yl)ethyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.1 g,0.73 mmol) in N,N-dimethylformamide (2 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.088 g, 0.29 mmol).After stirring at 55° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain the titlecompound (0.092 g, 48%); ¹H NMR (DMSO-d₆): δ 1.41 (br, 2H), 1.52-1.62(m, 6H), 1.82 (t, 2H, J=6.4 Hz), 2.34 (t, 2H, J=6.8 Hz), 2.56-2.72 (m,6H), 3.34-3.38 (m, 4H), 3.85 (t, 2H, J=6.4 Hz), 4.59-4.63 (m, 4H), 5.02(s, 2H), 6.76 (t, 1H, J=7.2 Hz), 6.85 (d, 2H, J=8.4 Hz), 6.96 (d, 3H,J=3.6 Hz), 7.18-7.24 (m, 3H), 7.53-7.60 (m, 2H), 7.90-7.92 (m, 2H),10.81 (s, 1H); MS for C₃₈H₄₄N₆O₅ m/z 665.17 (M+H)⁺.

tert-Butyl4-oxo-3-(3-((2-oxo-2-(piperidin-1-yl)ethoxy)carbonyl)benzyl)-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of piperidine (0.084 mL, 0.86 mmol, d=0.862) stirring indichloromethane (4 mL) at 0° C., was added chloro acetylchloride (0.034mL, 0.43 mmol, d=1.419). After stirring at 0° C. for a hour, thereaction mixture was diluted with dichloromethane (25 mL), washed withdilute citric acid, water and brine. The organic phase was dried overMgSO₄, filtered and concentrated in vacuo to obtain2-chloro-1-(piperidin-1-yl)ethanone.

To a solution of 2-chloro-1-(piperidin-1-yl)ethanone inN,N-dimethylformamide (3 mL), was added tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.2 g, 0.43mmol) and potassium carbonate (0.119 g, 0.86 mmol). After stirring at65° C. for 18 hours, the reaction mixture was diluted with ethyl acetate(25 mL), washed with dilute citric acid, water and brine. The organicphase was dried over MgSO₄, filtered and isolated by preparatory TLC(10% methanol/dichloromethane) to obtain the title compound (0.17 g,67%); ¹H NMR (DMSO-d₆): δ 1.45 (s, 9H), 1.52-1.58 (m, 8H), 2.32-2.45 (m,2H), 3.35-3.40 (m, 6H), 3.88 (br, 2H), 4.63-4.66 (m, 4H), 5.03 (s, 2H),6.68 (d, 2H, J=8 Hz), 6.70 (t, 1H, J=7.6 Hz), 7.17 (t, 2H, J=8 Hz),7.56-7.60 (m, 2H), 7.91-7.93 (m, 2H); MS for C₃₃H₄₂N₄O₆ m/z 591.08(M+H)⁺.

Example 22 Compound 33 (S)-methyl2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate

A mixture of (S)-methyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (159mg, 0.383 mmol, 1 equiv),1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (115.6 mg, 0.38 mmol,1 equiv) and potassium carbonate (158.6 mg, 1.148 mmol, 3 equiv) inN,N-dimethylformamide was heated at 65° C. for 16 h. The reaction wascooled to ambient temperature and worked up using 5% methanol indichloromethane and water. The organic layer was dried over MgSO₄, andconcentrated in vacuo under a high vacuum. The crude mixture waspurified by preparatory thin layer chromatography using 7% methanol indichloromethane. The purified extract was lyophilized to afford thetitle compound as a white solid (25 mg, <10%); ¹H NMR (400 MHz,DMSO-d₆): δ 1.61 (bs, 2H), 1.84 (bs, 2H), 2.46 (bs, 4H); 2.50-2.51 (m,4H); 3.74 (s, 3H); 3.85 (t, 2H, J=7.2 and 6.4 Hz); 4.15 (d, 1H, J=4.8Hz); 4.80 (d, 1H, J=4.8 Hz); 5.89 (s, 1H)); 6.79-6.85 (m, 3H); 6.97 (d,3H, J=2.8 Hz); 7.16-7.18 (m, 1H); 7.23 (t, 2H, J=7.2 and 8.8 Hz);7.39-7.46 (m, 5H); 10.82 (s, 1H); MS for C₃₂H₃₅N₅O₄ m/z 554.11 (M+H)⁺.

Preparation of (S)-methyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate

(R)-methyl 2-amino-2-phenylacetate (5 g, 24.8 mmol, 1 equiv) wasdissolved in a mixture of 48% Hydrogen bromide (13 ml, 198 mmol, 8equiv) and water (19 ml). An aqueous solution of sodium nitrite (5.48 g,79.36 mmol, 3.2 equiv) was added slowly and the mixture stirred at 0° C.for 1.5 h. The reaction was degassed in vaccuo and extracted with ether.The organic layer was further washed with water and brine, dried overMgSO₄, and concentrated in vacuo. The resulting residue was purifiedusing the Biotage flash chromatography system (SNAP 100 g cartridge,R_(f)=0.5, 10% ethyl acetate/hexanes) to afford the (S)-methyl2-bromo-2-phenylacetate as a light yellow oil (2.3 g, 40% yield). ¹H NMR(400 MHz, DMSO-d₆): δ 3.72 (s, 3H); 5.95 (s, 1H); 7.36-7.42 (m, 3H);7.532 (d, 2H, J=1.2 Hz); 7.56 (d, 1H, J=2 Hz). MS for C₉H₉BrO₂ m/z229.98 (M+H)⁺.

A mixture of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (300 mg, 0.905mmol, 1 equiv), (S)-methyl 2-bromo-2-phenylacetate (207.4 mg, 0.905mmol, 1 equiv) and potassium carbonate (312.7 mg, 2.26 mmol, 2.5 equiv)in N,N-dimethylformamide was stirred at 65° C. for 2 hours. The reactionmixture was cooled to ambient temperature and the mixture waspartitioned between ethyl acetate and water. The organic layer wasfurther washed with brine, dried over MgSO₄, and concentrated in vacuo.The resulting residue was purified using the Biotage flashchromatography system (SNAP 50 g cartridge, R_(f)=0.4, 20% ethylacetate/hexanes) to afford (S)-tert-butyl3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylateas an oil (183 mg, 42.3%). MS for C₂₇H₃₃N₃O₅ m/z 479.57 (M+H)⁺.

Deprotection of (S)-tert-butyl3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(183 mg, 0.382 mmol, 1 equiv) was accomplwashed in 3 hours in thepresence of 4M hydrochloric acid in dioxane at ambient temperature. Theresulting mixture was concentrated and dried in vacuo to afford thehydrogen chloride salt of the title compound as a white solid (158 mg,quant); ¹H NMR (400 MHz, DMSO-d₆): δ 1.82 (d, 2H, J=14.4 Hz), 2.67-2.77(m, 2H); 2.93 (bs, 1H); 3.35-3.39 (m, 2H); 3.75 (s, 3H); 4.21 (d, 1H,J=4.8 Hz); 4.84 (d, 1H, J=4.4 Hz); 5.93 (s, 1H); 6.84 (t, 1H, J=7.2 Hz);6.96 (d, 2H, J=8 Hz); 7.21-7.25 (m, 2H); 7.41-7.47 (m, 4H); 7.53 (s,1H); 9.06 (bs, 1H); 9.14 (bs, 1H); MS for C₂₂H₂₅N₃O₃ m/z 380.01 (M+H)⁺.

Example 23 Compound 34 (R)-methyl2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate

A mixture of (R)-methyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (355mg, 0.854 mmol, 1 equiv),1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (258.06 mg, 0.854mmol, 1 equiv) and potassium carbonate (354.1 mg, 2.562 mmol, 3 equiv)in N,N-dimethylformamide was heated at 65° C. for 16 h. The reaction wascooled to ambient temperature and worked up using 5% methanol indichloromethane and water. The organic layer was dried over MgSO₄, andconcentrated in vacuo. The crude mixture was purified by preparatorythin layer chromatography using 7% methanol in dichloromethane. Thepurified extract was lyophilized to afford the title compound as a whitesolid (140 mg, ˜30%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.59 (t, 2H, J=15.2Hz, J=14.8 Hz), 1.81 (bs, 2H), 2.33 (bs, 4H); 2.54-2.64 (m, 2H);2.69-2.73 (m, 2H); 3.74 (s, 3H); 3.84 (t, 2H, J=6.8 Hz); 4.14 (d, 1H,J=4.4 Hz); 4.79 (d, 1H, J=4.8 Hz); 5.89 (s, 1H)); 6.78-6.84 (m, 3H);6.97 (d, 3H, J=2.4 Hz); 7.16-7.18 (m, 1H); 7.23 (t, 2H, J=7.2 and 8.8Hz); 7.39-7.46 (m, 5H); 10.82 (s, 1H; MS for C₃₂H₃₅N₅O₄ m/z 554.07(M+H)⁺.

Preparation of (R)-methyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate

(S)-methyl 2-amino-2-phenylacetate (5 g, 24.8 mmol, 1 equiv) wasdissolved in a mixture of 48% hydrogen bromide (13 ml, 198 mmol, 8equiv) and water (19 ml). An aqueous solution of sodium nitrite (5.48 g,79.36 mmol, 3.2 equiv) was added slowly and the mixture stirred at 0° C.for 1.5 h. The reaction was degassed in vacuo and extracted with ether.The organic layer was further washed with water and brine, dried overMgSO₄, and concentrated in vacuo. The resulting residue was purifiedusing the Biotage flash chromatography system (SNAP 100 g cartridge,R_(f)=0.5, gradient—1%-10% ethyl acetate/hexanes) to afford the(R)-methyl 2-bromo-2-phenylacetate as a light yellow oil (2.3 g, 40%yield).). ¹H NMR (400 MHz, DMSO-d₆): δ 3.72 (s, 3H); 5.95 (s, 1H);7.36-7.42 (m, 3H); 7.54 (d, 2H, J=1.6 Hz); 7.56 (d, 1H, J=2 Hz). MS forC₉H₉BrO₂ m/z 229.98 (M+H)⁺.

A mixture of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (400 mg, 1.21mmol, 1 equiv), (R)-methyl 2-bromo-2-phenylacetate (276.6 mg, 1.21 mmol,1 equiv) and potassium carbonate (418.1 mg, 3.025 mmol, 2.5 equiv) inN,N-dimethylformamide was stirred at 65° C. for 3.5 hours. The reactionmixture was cooled to ambient temperature and the mixture waspartitioned between ethyl acetate and water. The organic layer wasfurther washed with brine, dried over MgSO₄, and concentrated in vacuo.The resulting residue was purified using the Biotage flashchromatography system (SNAP 50 g cartridge, R_(f)=0.4, gradient—5%-20%ethyl acetate/hexanes) to afford (R)-tert-butyl3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylateas an oil (410 mg, 71.1%). MS for C₂₇H₃₃N₃O₅ m/z 479.57 (M+H)⁺.

Deprotection of (R)-tert-butyl3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(410 mg, 0.86 mmol, 1 equiv) was accomplished in 3 hours in the presenceof 4M hydrogen chloride solution in dioxane at ambient temperature. Theresulting mixture was concentrated and dried in vacuo to afford thehydrogen chloride salt of the title compound as a white solid (355 mg,quant); ¹H NMR (400 MHz, DMSO-d₆): δ 1.83 (d, 2H, J=14.0 Hz), 2.66-2.74(m, 2H); 3.44-3.51 (m, 4H); 3.75 (s, 3H); 4.21 (d, 1H, J=4.4 Hz); 4.84(d, 1H, J=4.8 Hz); 5.93 (s, 1H); 6.85 (t, 1H, J=7.2 and 7.6 Hz); 6.95(d, 2H, J=8 Hz); 7.21-7.25 (m, 2H); 7.39-7.45 (m, 4H); 7.53 (s, 1H);8.97-9.04 (m, 2H); MS for C₂₂H₂₅N₃O₃ m/z 380.03 (M+H)⁺.

Example 24 Compound 35 2-(4-Methylpiperazin-1-yl)-2-oxoethyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.16 g, 0.26 mmol) was added 4M solution of HCl in dioxane (3 mL).After stirring at room temperature for 2 hours, the reaction mixture wasconcentrated in vacuo to obtain 2-(4-methylpiperazin-1-yl)-2-oxoethyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.09 g,0.65 mmol) in N,N-dimethylformamide (2 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.079 g, 0.26 mmol).After stirring at 55° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated byreverse phase HPLC to obtain the title compound (0.052 g, 29%); ¹H NMR(DMSO-d₆): δ 1.61 (d, 2H, J=13.6 Hz), 1.83 (t, 2H, J=6.4 Hz), 2.17 (s,3H), 2.24-2.36 (m, 6H), 2.52-2.72 (m, 6H), 3.32-3.40 (m, 4H), 3.85 (t,2H, J=6.8 Hz), 4.61 (d, 4H, J=14.4 Hz), 5.04 (s, 2H), 6.76 (t, 1H, J=7.2Hz), 6.85 (d, 2H, J=8 Hz), 6.96 (d, 3H, J=2 Hz), 7.17-7.24 (m, 3H),7.53-7.60 (m, 2H), 7.90-7.92 (m, 2H), 10.82 (s, 1H); MS for C₃₈H₄₅N₇O₅m/z 680.17 (M+H)⁺.

tert-Butyl3-(3-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of N-methylpiperazine (0.096 mL, 0.86 mmol, d=0.902)stirring in dichloromethane (5 mL) at 0° C., was added chloroacetylchloride (0.034 mL, 0.43 mmol, d=1.419). After stirring at 0° C.for an hour, the reaction mixture was diluted with dichloromethane (25mL), washed with dilute citric acid, water and brine. The organic phasewas dried over MgSO₄, filtered and concentrated in vacuo to obtain2-chloro-1-(4-methylpiperazin-1-yl)ethanone.

To a solution of 2-chloro-1-(4-methylpiperazin-1-yl)ethanone inN,N-dimethylformamide (3 mL), was added tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.2 g, 0.43mmol) and potassium carbonate (0.119 g, 0.86 mmol). After stirring at65° C. for 18 hours, the reaction mixture was diluted with ethyl acetate(25 mL), washed with dilute citric acid, water and brine. The organicphase was dried over MgSO₄, filtered and isolated by Biotage flashchromatography (2-20% methanol/dichloromethane) to obtain the titlecompound (0.16 g, 62%); ¹H NMR (DMSO-d₆): δ 1.45 (s, 9H), 1.64 (t, 2H,J=12.8 Hz), 2.18 (s, 3H), 2.25-2.45 (m, 6H), 3.41-3.50 (m, 6H), 3.85(br, 2H), 4.60-4.65 (m, 4H), 5.05 (s, 2H), 6.64-6.69 (m, 2H), 6.76-6.79(m, 1H), 7.13-7.19 (m, 2H), 7.54-7.60 (m, 2H), 7.91-7.93 (m, 2H); MS forC₃₃H₄₃N₅O₆ m/z 606.08 (M+H)⁺.

Example 25 Compound 39(R)-2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylaceticacid

A solution of (R)-methyl2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate(105 mg, 0.189 mmol, 1 equiv) and lithium hydroxide (15.9 mg, 0.38 mmol,2.0 equiv) in a 3:1 mixture of methanol and water (5 ml t/v) was stirredat ambient temperature for 24 hrs. The reaction was concentrated invacuo and purified using preparatory high performance liquidchromatography. The combined pure fractions were lyophilized to affordthe acetate salt of the title compound as a white solid (21 mg, 20%); ¹HNMR (400 MHz, DMSO-d₆): δ 1.57-1.66 (m, 2H), 1.87-1.91 (m, 2H);2.79-2.85 (m, 4H); 3.27-3.42 (bs, 4H); 3.85 (t, 2H, J=6.8 Hz); 4.11 (d,1H, J=4.8 Hz); 4.91 (d, 1H, J=4.8 Hz); 5.71 (s, 1H); 6.76-6.82 (m, 3H);6.97-6.98 (m, 3H); 7.17-7.23 (m, 3H); 7.35-7.43 (m, 5H); 10.83 (s, 1H);12.5 (bs, 1H); MS for C₃₁H₃₃ClN₅O₄ 540.01 (M+H)⁺.

Preparation of (R)-methyl2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate

A mixture of (R)-methyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (355mg, 0.854 mmol, 1 equiv),1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (258.06 mg, 0.854mmol, 1 equiv) and potassium carbonate (354.1 mg, 2.562 mmol, 3 equiv)in N,N-dimethylformamide was heated at 65° C. for 16 h. The reaction wascooled to ambient temperature and worked up using 5% methanol indichloromethane and water. The organic layer was dried over MgSO₄, andconcentrated in vacuo. The crude mixture was purified by preparatorythin layer chromatography using 7% methanol in dichloromethane. Thepurified extract was lyophilized to afford the title compound as a whitesolid (140 mg, ˜30%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.59 (t, 2H, J=15.2and 14.8 Hz), 1.81 (bs, 2H), 2.33 (bs, 4H); 2.54-2.64 (m, 2H); 2.69-2.73(m, 2H); 3.74 (s, 3H); 3.84 (t, 2H, J=6.8 Hz); 4.14 (d, 1H, J=4.4 Hz);4.79 (d, 1H, J=4.8 Hz); 5.89 (s, 1H)); 6.78-6.84 (m, 3H); 6.97 (d, 3H,J=2.4 Hz); 7.16-7.18 (m, 1H); 7.23 (t, 2H, J=7.2 and 8.8 Hz); 7.39-7.46(m, 5H); 10.82 (s, 1H); MS for C₃₂H₃₅N₅O₄ m/z 554.07 (M+H)⁺.

Preparation of (R)-methyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-O-2-phenylacetate

(S)-methyl 2-amino-2-phenylacetate (5 g, 24.8 mmol, 1 equiv) wasdwassolved in a mixture of 48% hydrogen bromide (13 ml, 198 mmol, 8equiv) and water (19 ml). An aqueous solution of sodium nitrite (5.48 g,79.36 mmol, 3.2 equiv) was added slowly and the mixture stirred at 0° C.for 1.5 h. The reaction was degassed in vacuo and extracted with ether.The organic layer was further washed with water and brine, dried overMgSO₄, and concentrated in vacuo. The resulting residue was purifiedusing the Biotage flash chromatography system (SNAP 100 g cartridge,R_(f)=0.5, gradient—1%-10% ethyl acetate in hexanes) to afford the(R)-methyl 2-bromo-2-phenylacetate as a light yellow oil (2.3 g, 40%yield); ¹H NMR (400 MHz, DMSO-d₆): δ 3.72 (s, 3H); 5.95 (s, 1H);7.36-7.42 (m, 3H); 7.54 (d, 2H, J=1.6 Hz); 7.56 (d, 1H, J=2 Hz); MS forC₉H₉BrO₂ m/z 229.98 (M+H)⁺.

A mixture of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (400 mg, 1.21mmol, 1 equiv), (R)-methyl 2-bromo-2-phenylacetate (276.6 mg, 1.21 mmol,1 equiv) and potassium carbonate (418.1 mg, 3.025 mmol, 2.5 equiv) inN,N-dimethylformamide was stirred at 65° C. for 3.5 hours. The reactionmixture was cooled to ambient temperature and the mixture waspartitioned between ethyl acetate and water. The organic layer wasfurther washed with brine, dried over MgSO₄, and concentrated in vacuo.The resulting residue was purified using the Biotage flashchromatography system (SNAP 50 g cartridge, R_(f)=0.4, gradient—2%-20%ethyl acetate/hexanes,) to afford (R)-tert-butyl3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylateas an oil (410 mg, 71.1%); MS for C₂₇H₃₃N₃O₅ m/z 479.57 (M+H)⁺.

Deprotection of (R)-tert-butyl3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(410 mg, 0.86 mmol, 1 equiv) was accomplished in 3 hours in the presenceof 4M hydrogen chloride solution in dioxane at ambient temperature. Theresulting mixture was concentrated and dried in vacuo to afford thehydrogen chloride salt of the title compound as a white solid (355 mg,quant); ¹H NMR (400 MHz, DMSO-d₆): δ 1.81-1.85 (d, 2H, J=14.0 Hz),2.66-2.74 (m, 2H); 3.44-3.51 (m, 4H); 3.75 (s, 3H); 4.21 (d, 1H, J=4.4Hz); 4.84 (d, 1H, J=4.8 Hz); 5.93 (s, 1H); 6.85 (t, 1H, J=7.2 and 7.6Hz); 6.95 (d, 2H, J=8 Hz); 7.21-7.25 (m, 2H); 7.39-7.45 (m, 4H); 7.53(s, 1H); 8.97-9.04 (m, 2H); MS for C₂₂H₂₅N₃O₃ m/z 380.03 (M+H)⁺.

Example 26 Compound 40(S)-2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylaceticacid

A solution of (S)-methyl2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate(295 mg, 0.533 mmol, 1 equiv) and lithium hydroxide (44.77 mg, 1.07mmol, 2.0 equiv) in a 3:1 mixture of methanol and water (5 ml t/v) wasstirred at ambient temperature for 24 hrs. The reaction was concentratedin vacuo and purified using preparatory high performance liquidchromatography. The combined pure fractions were lyophilized to affordthe acetate salt of the title compound as a white solid (61 mg, 21%); ¹HNMR (400 MHz, DMSO-d₆): δ 1.57-1.66 (m, 2H), 1.87-1.91 (m, 2H);2.79-2.86 (m, 4H); 3.27-3.42 (bs, 4H); 3.85 (t, 2H, J=6.8 and 6.4 Hz);4.11 (d, 1H, J=4.8 Hz); 4.94 (d, 1H, J=3.2 Hz); 5.68 (s, 1H); 6.74-6.80(m, 3H); 6.95-6.98 (m, 3H); 7.17-7.21 (m, 3H); 7.33-7.42 (m, 5H); 10.85(s, 1H); 12.5 (bs, 1H); MS for C₃₁H₃₃ClN₅O₄ m/z 540.07 (M+H)⁺.

Preparation of (S)-methyl2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate

A mixture of (S)-methyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (159mg, 0.383 mmol, 1 equiv),1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (115.6 mg, 0.38 mmol,1 equiv) and potassium carbonate (158.6 mg, 1.148 mmol, 3 equiv) inN,N-dimethylformamide was heated at 65° C. for 16 h. The reaction wascooled to ambient temperature and worked up using 5% methanol indichloromethane and water. The organic layer was dried over MgSO₄, andconcentrated in vacuo. The crude mixture was purified using preparatorythin layer chromatography in 7% methanol in dichloromethane. Thepurified extract was lyophilized to afford the title compound as a whitesolid (25 mg, <10%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.61 (bs, 2H), 1.84(bs, 2H), 2.46 (bs, 4H); 2.50-2.51 (m, 4H); 3.74 (s, 3H); 3.85 (t, 2H,J=7.2 and 6.4 Hz); 4.15 (d, 1H, J=4.8 Hz); 4.80 (d, 1H, J=4.8 Hz); 5.89(s, 1H)); 6.79-6.85 (m, 3H); 6.97 (d, 3H, J=2.8 Hz); 7.16-7.18 (m, 1H);7.23 (t, 2H, J=7.2 and 8.8 Hz); 7.39-7.46 (m, 5H); 10.82 (s, 1H); MS forC₃₂H₃₅N₅O₄ m/z 554.11 (M+H)⁺.

Preparation of (S)-methyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate

(R)-methyl 2-amino-2-phenylacetate (5 g, 24.8 mmol, 1 equiv) wasdissolved in a mixture of 48% hydrogen bromide (13 ml, 198 mmol, 8equiv) and water (19 ml). An aqueous solution of sodium nitrite (5.48 g,79.36 mmol, 3.2 equiv) was added slowly and the mixture stirred at 0° C.for 1.5 h. The reaction was degassed in vacuo and extracted with ether.The organic layer was further washed with water and brine, dried overMgSO₄, and concentrated in vacuo. The resulting residue was purifiedusing the Biotage flash chromatography system (SNAP 100 g cartridge,R_(f)=0.5, gradient—1%-10% ethyl acetate/hexanes) to afford the(S)-methyl 2-bromo-2-phenylacetate as a light yellow oil (2.3 g, 40%yield); ¹H NMR (400 MHz, DMSO-d₆): δ 3.72 (s, 3H); 5.95 (s, 1H);7.36-7.42 (m, 3H); 7.53 (d, 2H, J=1.2 Hz); 7.56 (d, 1H, J=2 Hz); MS forC₉H₉BrO₂ m/z 229.98 (M+H)⁺.

A mixture of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (300 mg, 0.905mmol, 1 equiv), (S)-methyl 2-bromo-2-phenylacetate (207.4 mg, 0.905mmol, 1 equiv) and potassium carbonate (312.7 mg, 2.26 mmol, 2.5 equiv)in N,N-dimethylformamide was stirred at 65° C. for 2 hours. The reactionmixture was cooled to ambient temperature and the mixture waspartitioned between ethyl acetate and water. The organic layer wasfurther washed with brine, dried over MgSO₄, and concentrated in vacuo.The resulting residue was purified using a Biotage flash chromatographysystem (SNAP 50 g cartridge, R_(f)=0.4, gradient-2%-20% ethylacetate/hexanes) to afford (S)-tert-butyl3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylateas an oil (183 mg, 42.3%); MS for C₂₇H₃₃N₃O₅ m/z 479.57 (M+H)⁺.

Deprotection of (S)-tert-butyl3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(183 mg, 0.382 mmol, 1 equiv) was accomplished in 3 hours in thepresence of 4M hydrogen chloride solution in dioxane at ambienttemperature. The resulting mixture was concentrated and dried in vacuoto afford the hydrogen chloride salt of the title compound as a whitesolid (158 mg, quant); ¹H NMR (400 MHz, DMSO-d₆): δ 1.82 (d, 2H, J=14.4Hz), 2.67-2.77 (m, 2H); 2.93 (bs, 1H); 3.35-3.39 (m, 2H); 3.75 (s, 3H);4.21 (d, 1H, J=4.8 Hz); 4.84 (d, 1H, J=4.4 Hz); 5.93 (s, 1H); 6.84 (t,1H, J=7.2 Hz); 6.96 (d, 2H, J=8 Hz); 7.21-7.25 (m, 2H); 7.41-7.47 (m,4H); 7.53 (s, 1H); 9.06 (bs, 1H); 9.14 (bs, 1H); MS for C₂₂H₂₅N₃O₃ m/z399.93 (M+H)⁺.

Example 27 Compound 42 Methyl3-((1-(4-fluorophenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl1-(4-fluorophenyl)-3-(3-(methoxycarbonyl)benzyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.42 g, 0.84 mmol) was added 4M solution of HCl in dioxane (5 mL).After stirring at room temperature for 2 hours, the reaction mixture wasconcentrated in vacuo to obtain methyl3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateas a hydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.290g, 2.1 mmol) in N,N-dimethylformamide (5 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.254 g, 0.84 mmol).After stirring at 55° C. for 60 hours, the reaction mixture was dilutedwith ethyl acetate (50 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain the product(0.085 g, 18%); ¹H NMR (DMSO-d₆): δ 1.61 (d, 2H, J=13.6 Hz), 1.83 (m,2H), 2.31-2.39 (m, 4H), 2.62-2.73 (m, 4H), 3.81-3.84 (s, 5H), 4.55-4.59(m, 4H) 6.90-6.91 (m, 2H), 6.96 (d, 2H, J=2.4 Hz), 7.07-7.15 (m, 4H),7.51-7.57 (m, 2H), 7.87-7.89 (m, 2H), 10.80 (s, 1H); MS for C₃₂H₃₄FN₅O₄m/z 572.07 (M+H)⁺.

tert-Butyl1-(4-fluorophenyl)-3-(3-(methoxycarbonyl)benzyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one(prepared according to methods described in U.S. Pat. No. 3,155,670 andU.S. Pat. No. 3,238,216) (2 g, 8.02 mmol) in dichloromethane (20 mL) andN,N-diisopropylethylenediamine (2.8 mL, 16.04 mmol, d=0.742), was addeddi-tert-butyl dicarbonate (1.77 g, 8.10 mmol). After stirring at roomtemperature for 18 hours, the reaction mixture was diluted withdichloromethane (100 mL), washed with dilute citric acid, water andbrine. The organic phase was dried over MgSO₄, filtered and concentratedto obtain of tert-butyl1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.8g, 99%).

To a solution of tert-butyl1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.4g, 1.14 mmol) and potassium carbonate (0.124 g, 0.9 mmol) inN,N-dimethylformamide (4 mL), was added methyl 3-(bromomethyl)benzoate(0.315 g, 2.28 mmol). After stirring at 55° C. for 18 hours, thereaction mixture was diluted with ethyl acetate (50 mL), washed withdilute citric acid, water and brine. The organic phase was dried overMgSO₄, filtered and isolated by Biotage flash chromatography (10-100%ethyl acetate/hexanes) (0.43 g, 75%); ¹H NMR (DMSO-d₆): δ 1.45 (s, 9H),1.67 (d, 2H, J=14 Hz), 2.09-2.16 (m, 2H), 3.45 (br, 2H), 3.85-3.86 (m,5H), 4.52-4.62 (m, 4H), 6.71-6.81 (m, 2H), 7.05 (t, 2H, J=9.2 Hz),7.52-7.59 (m, 2H), 7.89-7.91 (m, 2H).

Example 28 Compound 433-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To a solution of methyl3-((1-(4-fluorophenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.25 g, 0.44 mmol) in methanol (3 mL) was added lithium hydroxidemonohydrate (0.037 g, 0.88 mmol) in water (1 mL). After stirring at roomtemperature for 18 h, the reaction mixture was concentrated in vacuo andisolated by reverse phase HPLC to obtain the title compound as anacetate salt (0.05 g, 13%); ¹H NMR (DMSO-d₆): δ 1.62 (d, 2H, J=13.2 Hz),1.81 (t, 2H, J=6.4 Hz), 2.27-2.37 (m, 4H), 2.50-2.69 (m, 4H), 3.83 (t,2H, J=6.8 Hz), 4.56 (d, 4H, J=15.2 Hz), 6.88-6.91 (m, 2H), 6.95-6.98 (m,3H), 7.08 (d, 2H, J=5.2 Hz), 7.13-7.16 (m, 1H), 7.47-7.52 (m, 2H),7.85-7.87 (m, 2H), 10.81 (s, 1H), 13.10 (br, 1H); MS for C₃₁H₃₂FN₅O₄ m/z558.02 (M+H)⁺.

Example 29 Compound 45 (S)-Quinuclidin-3-yl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a refluxing solution of methyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.2 g, 0.36 mmol) and (S)-3-quinuclidinol (0.184 g, 1.44 mmol) intoluene (2 mL), was added titanium(IV)-i-propoxide (0.105 mL, 0.36 mmol,d=0.97). After refluxing for 18 h, the reaction mixture was diluted with5% methanol/dichloromethane, washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated byreverse phase HPLC to obtain the title compound as an acetate salt (0.08g, 34%); ¹H NMR (DMSO-d₆): δ 1.32-1.36 (m, 1H), 1.51-1.54 (m, 4H),1.79-1.84 (m, 3H), 1.99-2.01 (m, 1H), 2.35 (t, 2H, J=6.8 Hz), 2.52-2.72(m, 11H), 3.15-3.21 (m, 1H), 3.85 (t, 2H, J=6.8 Hz), 4.61 (d, 4H, J=13.2Hz), 4.90-4.92 (m, 1H), 6.76 (t, 1H, J=6.8 Hz), 6.84 (d, 2H, J=8 Hz),6.96 (d, 3H, J=2.4 Hz), 7.17-7.24 (m, 3H), 7.52-7.59 (m, 2H), 7.87-7.92(m, 2H), 10.80 (br, 1H); MS for C₃₈H₄₄N₆O₄ m/z 649.11 (M+H)⁺.

Example 30 Compound 46 Methyl3-((4-oxo-8-(3-(2-oxobenzo[d]oxazol-3(2H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.23 g, 0.48 mmol) was added 4M solution of HCl in dioxane (5 mL).After stirring at room temperature for an hour, the reaction mixture wasconcentrated in vacuo to obtain methyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.166g, 1.2 mmol) in N,N-dimethylformamide (4 mL), was added3-(3-iodopropyl)benzo[d]oxazol-2(3H)-one (0.145 g, 0.48 mmol). Afterstirring at 55° C. for 18 hours, the reaction mixture was diluted withethyl acetate (50 mL), washed with water and brine. The organic phasewas dried over MgSO₄, filtered, concentrated and isolated by preparatoryTLC (10% methanol/dichloromethane) to obtain the product (0.21 g, 86%);¹H NMR (DMSO-d₆): δ 1.55 (d, 2H, J=14 Hz), 1.88 (t, 2H, J=6.8 Hz), 2.38(t, 2H, J=6.4 Hz), 2.43-2.46 (m, 2H), 2.63-2.65 (m, 4H), 3.85 (s, 3H),3.92 (t, 2H, J=6.4 Hz), 4.58 (d, 4H, J=14.8 Hz), 6.79 (t, 1H, J=7.6 Hz),6.84 (d, 2H, J=8 Hz), 7.10 (t, 1H, J=8 Hz), 7.19 (t, 1H, J=7.6 Hz),7.23-7.29 (m, 3H), 7.36 (d, 1H, J=7.2 Hz), 7.51-7.57 (m, 2H), 7.87-7.89(m, 2H); MS for C₃₂H₃₄N₄O₅ m/z 555.05 (M+H)⁺.

3-(3-Iodopropyl)benzo[d]oxazol-2 (3H)-one

To a solution of 2-benzoxazolinone (2.0 g, 14.8 mmol) and potassiumcarbonate (3.07 g, 22.2 mmol) in N,N-dimethylformamide (20 mL), wasadded 1-bromo-3-chloropropane (4.4 mL, 44.4 mmol, d=1.6). After stirringat 55° C. for 18 hours, the reaction mixture was diluted with ethylacetate (100 mL), washed with dilute citric acid, water and brine. Theorganic phase was dried over MgSO₄ and concentrated to obtain3-(3-chloropropyl)benzo[d]oxazol-2(3H)-one (3.1 g, 99%).

To a solution of 3-(3-chloropropyl)benzo[d]oxazol-2(3H)-one (3.04 g,14.36 mmol) in acetone (60 mL), was added sodium iodide (4.3 g, 28.73mmol). After refluxing for 60 hours, the reaction mixture was filtered.The filtrate was washed with water and dried to obtain the titlecompound (3.6 g, 83%); ¹H NMR (DMSO-d₆): δ 2.19-2.24 (m, 2H), 3.28 (t,2H, J=6.8 Hz), 3.87 (t, 2H, J=6.8 Hz), 7.11 (t, 1H, J=8 Hz), 7.22 (t,1H, J=8 Hz), 7.32 (t, 2H, J=8.4 Hz). MS for C₁₀H₁₀INO₂ m/z 304.33(M+H)⁺.

Example 31 Compound 47 Methyl3-((4-oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.24 g, 0.5 mmol) was added 4M solution of HCl in dioxane (5 mL). Afterstirring at room temperature for an hour, the reaction mixture wasconcentrated in vacuo to obtain methyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.173g, 1.25 mmol) in N,N-dimethylformamide (4 mL), was added3-(3-iodopropyl)benzo[d]thiazol-2(3H)-one (0.16 g, 0.5 mmol). Afterstirring at 55° C. for 18 hours, the reaction mixture was diluted withethyl acetate (50 mL), washed with water and brine. The organic phasewas dried over MgSO₄, filtered, concentrated and isolated by preparatoryTLC (10% methanol/dichloromethane) to obtain the product (0.25 g, 88%);¹H NMR (DMSO-d₆): δ 1.59 (d, 2H, J=12.8 Hz), 1.84 (t, 2H, J=6.8 Hz),2.38 (t, 2H, J=6.4 Hz), 2.45-2.49 (m, 2H), 2.64-2.69 (m, 4H), 3.85 (s,3H), 4.04 (t, 2H, J=6.8 Hz), 4.59 (d, 4H, J=13.2 Hz), 6.78 (t, 1H, J=7.2Hz), 6.85 (d, 2H, J=7.6 Hz), 7.16-7.25 (m, 3H), 7.33 (t, 1H, J=7.6 Hz),7.46 (d, 1H, J=7.2 Hz), 7.51-7.58 (m, 2H), 7.64 (d, 1H, J=7.6 Hz),7.87-7.90 (m, 2H); MS for C₃₂H₃₄N₄O₄S m/z 571.05 (M+H)⁺.

3-(3-Iodopropyl)benzo[d]thiazol-2(3H)-one

To a solution of 2-hydroxybenzothiazole (2.0 g, 13.2 mmol) and potassiumcarbonate (2.74 g, 19.8 mmol) in N,N-dimethylformamide (20 mL), wasadded 1-bromo-3-chloropropane (3.92 mL, 39.7 mmol, d=1.6). Afterstirring at 55° C. for 18 hours, the reaction mixture was diluted withethyl acetate (100 mL), washed with dilute citric acid, water and brine.The organic phase was dried over MgSO₄ and concentrated to obtain3-(3-chloropropyl)benzo[d]thiazol-2(3H)-one (2.86 g, 95%).

To a solution of 3-(3-chloropropyl)benzo[d]thiazol-2(3H)-one (2.86 g,12.56 mmol) in acetone (50 mL), was added sodium iodide (3.77 g, 25.12mmol). After refluxing for 60 hours, the reaction mixture was filtered.The filtrate was washed with water and dried to obtain the titlecompound (3.85 g, 83%); ¹H NMR (DMSO-d₆): δ 2.13-2.16 (m, 2H), 3.28 (t,2H, J=6.8 Hz), 4.05 (t, 2H, J=6.8 Hz), 7.18-7.22 (m, 1H), 7.38-7.39 (m,2H), 7.66 (dt, 1H, J=7.6 and 0.8 Hz).

Example 32 Compound 48 methyl3-((8-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of methyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (500mg, 1.2 mmol, 1 equiv), 1-(4-fluorophenyl)-4-iodobutan-1-one (351.1 mg,1.2 mmol, 1 equiv), and potassium carbonate (497.6 mg, 3.6 mmol, 3equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. Thereaction was cooled to ambient temperature and partitioned between ethylacetate and water. The organic layer was dried over MgSO₄, andconcentrated in vacuo. The crude was purified using preparatory thinlayer chromatography in 10% methanol in dichloromethane followed by apurification using preparatory high performance liquid chromatography toafford the acetate salt of the title compound as a yellow powder (65 mg,˜10%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.58 (d, 2H, J=14 Hz), 1.81-1.88 (m,2H); 2.39-2.47 (m, 4H); 2.67-2.75 (m, 4H); 3.04 (t, 2H, J=6.4 and 7.2Hz); 3.84 (s, 3H); 4.57 (s, 2H); 4.61 (s, 2H); 6.74-6.77 (m, 3H);7.14-7.18 (m, 2H); 7.32-7.37 (m, 2H); 7.52-7.58 (m, 2H); 7.88-7.90 (m,2H); 8.05-8.08 (m, 2H); 10.82 (s, 1H); MS for C₃₂H₃₄FN₃O₄ m/z 544.02(M+H)⁺.

Preparation of methyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2 g, 6.02mmol, 1 equiv), methyl 3-(bromomethyl)benzoate (1.38 g, 6.02 mmol, 1equiv) and potassium carbonate (1.25 g, 9.03 mmol, 1.5 equiv) inN,N-dimethylformamide was heated at 65° C. for 16 h. Upon cooling themixture was partitioned between ethyl acetate and water. The organiclayer was further washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified using the Biotage flashchromatography system (SNAP 50 g cartridge, R_(f)=0.5, gradient—10%-50%ethyl acetate in hexanes) to afford tert-butyl3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylateas a white solid (1.67 g, 58%); MS for C₂₇H₃₃N₃O₅ m/z 479.24 (M+H)⁺.

A solution of tert-butyl3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(1.2 g, 2.5 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxanewas stirred at ambient temperature for 3 h. The reaction mixture wasconcentrated and dried in vacuo to afford the hydrogen chloride salt ofthe title compound as a white powder (0.95 g, quant.); MS for C₂₂H₂₅N₃O₃m/z 379.19 (M+H)⁺.

Preparation of 1-(4-fluorophenyl)-4-iodobutan-1-one

Sodium iodide (7.47 g, 49.84 mmol, 2 equiv) was added to a solution of4-chloro-1-(4-fluorophenyl)butan-1-one (5 g, 24.92 mmol, 1 equiv) inacetone. The reaction mixture was refluxed for 16 h. After cooling toambient temperature, it was evaporated under reduced pressure. Theresidue was partitioned between ethyl acetate and sodium bisulfite,followed by a wash with brine. The organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The crude residue was purified usingthe Biotage flash chromatography system (SNAP 100 g cartridge,R_(f)=0.5, gradient—1%-10% ethyl acetate in hexanes) to afford the titlecompound as a clear oil (5.62 g, 77%). The bottle containing thecompound was wrapped in aluminium foil and stored in the freezer toavoid further darkening of the mixture; MS for C₁₀H₁₀FIO m/z 291.98(M+H)⁺.

Example 33 Compound 493-((8-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of methyl3-((8-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(450 mg, 0.828 mmol, 1 equiv) and lithium hydroxide (34.7 mg, 1.656mmol, 2.0 equiv) in a 3:1 mixture of methanol and water (5 ml t/v) wasstirred at 35° C. for 24 hrs. The reaction was concentrated in vacuo andpurified using preparatory high performance liquid chromatography. Thecombined pure fractions were lyophilized to afford the acetate salt ofthe title compound as a white solid (100 mg, 25%); ¹H NMR (400 MHz,DMSO-d₆): δ 1.59 (d, 2H, J=13.6 Hz), 1.84 (t, 2H, J=7.2 and 6.8 Hz);2.45-2.46 (m, 4H); 2.72-2.78 (m, 4H); 3.05 (t, 2H, J=6.8 and 7.2 Hz);4.57 (s, 2H); 4.60 (s, 2H); 6.72-6.78 (m, 3H); 7.12-7.16 (m, 2H);7.32-7.36 (m, 2H); 7.47-7.53 (m, 2H); 7.86-7.88 (m, 2H); 8.04-8.08 (m,2H); 10.82 (s, 1H); 12.9 (bs, 1H); MS for C₃₁H₃₂FN₃O₄ m/z 529.99 (M+H)⁺.

Example 34 Compound 50 methyl3-((8-(3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of methyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (400mg, 0.962 mmol, 1 equiv),1-(3-iodopropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (304.8 mg, 0.962mmol, 1 equiv), and potassium carbonate (399 mg, 2.88 mmol, 3 equiv) washeated at 65° C. for 16 h. The reaction was cooled to ambienttemperature and worked up using ethyl acetate and water. The organiclayer was dried over MgSO₄, filtered and concentrated in vacuo. Thecrude residue was purified using preparatory thin layer chromatographyin 5% methanol in dichloromethane to afford the title compound as an oil(427 mg, 78%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.61 (d, 2H, J=13.2 Hz),1.85 (t, 2H, J=7.2 and 6.8 Hz); 2.34 (d, 2H, J=6.4 Hz); 2.64-2.66 (m,2H); 2.89 (s, 3H); 3.843 (s, 3H); 3.91 (t, 2H, J=6.4 and 6.8 Hz); 4.58(s, 2H); 4.62 (s, 2H); 6.78 (t, 1H, J=7.2 Hz); 6.86 (d, 2H, J=8.8 Hz);7.01-7.07 (m, 2H); 7.13-7.14 (m, 1H); 7.21-7.26 (m, 3H); 7.52-7.58 (m,2H); 7.88 (s, 1H); 7.90 (s, 1H); MS for C₃₃H₃₇N₅O₄ m/z 568.13 (M+H)⁺.

Preparation of 1-(3-iodopropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

A mixture of 1-methyl-1H-benzo[d]imidazol-2(3H)-one (2 g, 13.5 mmol, 1equiv), 1-bromo-3-chloropropane (3.98 ml, 40.5 mmol, 3 equiv), andpotassium carbonate (2.79 g, 20.25 mmol, 1.5 equiv) inN,N-dimethylformamide was heated at 65° C. for 16 h. The reaction wascooled to ambient temperature and diluted with ethyl acetate. Afterbeing washed with water and brine, the organic layer was dried overMgSO₄, filtered, and concentrated in vacuo. The resulting residue waspurified using the Biotage chromatography system (SNAP 100 g cartridge,R_(f)=0.6, gradient—10%-50% ethyl acetate/hexanes) to afford1-(3-chloropropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one as a clear oil(2.57 g, 85%); ¹H NMR (400 MHz, DMSO-d₆): δ 2.05-2.12 (m, 1H); 2.14-2.21(m, 1H); 3.32 (s, 3H); 3.53 (t, 1H, J=6.8 and 6.4 Hz); 3.66 (t, 1H,J=6.4 Hz); 3.92-3.97 (m, 2H); 7.05-7.09 (m, 2H); 7.12-7.16 (m, 1H);7.17-7.21 (m, 1H); MS for C₁₁H₁₃ClN₂O m/z 226.07 (M+H)⁺.

Sodium iodide (3.43 g, 22.89 mmol, 2 equiv) was added to a solution of1-(3-chloropropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (2.57 g, 11.44mmol, 1 equiv) in acetone. The reaction mixture was refluxed for 16 h.After cooling to ambient temperature, it was evaporated under reducedpressure to remove all the acetone. The residue was worked up usingethyl acetate and water, followed by a wash with brine. The organiclayer was dried over MgSO₄, filtered and concentrated in vacuo to affordthe title compound as a red oil (3.62 g, quant); ¹H NMR (400 MHz,DMSO-d₆): δ 2.12-2.19 (m, 2H); 3.24 (t, 2H, J=7.2 and 6.8 u Hz); 3.28(s, 3H); 3.89 (t, 2H, J=6.8 Hz); 7.04-7.09 (m, 2H); 7.13-7.16 (m, 1H);7.18-7.22 (m, 1H); MS for C₁₁H₁₃IN₂O m/z 316.89 (M+H)⁺.

Example 35 Compound 523-((4-Oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To a solution of methyl3-((4-oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.17 g, 0.3 mmol) in methanol (3 mL) was added lithium hydroxidemonohydrate (0.025 g, 0.6 mmol) in water (1 mL). After stirring at roomtemperature for 18 h, the reaction mixture was concentrated in vacuo andisolated by preparatory TLC (10% methanol/dichloromethane) to obtain thetitle compound (0.06 g, 36%); ¹H NMR (DMSO-d₆): δ 1.60 (d, 2H, J=14 Hz),1.85 (t, 2H, J=5.6 Hz), 2.48-2.53 (m, 7H), 2.66-2.75 (m, 4H), 4.04 (t,2H, J=8.4 Hz), 4.59 (d, 2H, J=8.4 Hz), 6.77 (t, 1H, J=7.6 Hz), 6.85 (d,2H, J=8.4 Hz), 7.18-7.24 (m, 3H), 7.33 (t, 1H, J=7.2 Hz), 7.45-7.51 (m,3H), 7.64 (d, 1H, J=7.2 Hz), 7.85 (d, 2H, J=8 Hz); MS for C₃₁H₃₂N₄O₄Sm/z 556.95 (M+H)⁺.

Example 36 Compound 55 Methyl3-((1-(4-methoxyphenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-(methoxycarbonyl)benzyl)-1-(4-methoxyphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.47 g, 0.92 mmol) was added 4M solution of HCl in dioxane (10 mL).After stirring at room temperature for 2 hours, the reaction mixture wasconcentrated in vacuo to obtain methyl3-((1-(4-methoxyphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateas a hydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.318g, 2.3 mmol) in N,N-dimethylformamide (5 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.278 g, 0.92 mmol).After stirring at 55° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (25 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated by pTLC(10% methanol/dichloromethane) to obtain the product (0.43 g, 80%); ¹HNMR (DMSO-d₆): δ 1.65 (d, 2H, J=8.8 Hz), 1.76 (t, 2H, J=6.4 Hz),1.95-2.01 (m, 2H), 2.29 (t, 2H, J=7.6 Hz), 2.53-2.59 (m, 4H), 3.68 (s,3H), 3.79 (t, 2H, J=6.4 Hz), 3.84 (s, 3H), 4.54 (d, 4H, J=31.2 Hz), 6.85(d, 2H, J=8.8 Hz), 6.93-6.97 (m, 5H), 7.10 (m, 1H), 7.51-7.57 (m, 2H),7.88-7.89 (m, 2H), 10.78 (s, 1H); MS for C₃₃H₃₇N₅O₅ m/z 584.04 (M+H)⁺.

tert-Butyl3-(3-(methoxycarbonyl)benzyl)-1-(4-methoxyphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of 1-(4-methoxyphenyl)-1,3,8-triazaspiro[4.5]decan-4-one(3.0 g, 11.5 mmol) in dichloromethane (50 mL) andN,N-diisopropylethylenediamine (4.0 mL, 23 mmol, d=0.742), was addeddi-tert-butyl dicarbonate (2.53 g, 11.6 mmol). After stirring at roomtemperature for 18 hours, the reaction mixture was diluted withdichloromethane (100 mL), washed with dilute citric acid, water andbrine. The organic phase was dried over MgSO₄, filtered and concentratedto obtain tert-butyl1-(4-methoxyphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate(4.1 g, 99%).

To a solution of tert-butyl1-(4-methoxyphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate(prepared according to methods described in U.S. Pat. No. 3,155,670 andU.S. Pat. No. 3,238,216) (1.3 g, 3.6 mmol) and potassium carbonate (1.0g, 7.2 mmol) in N,N-dimethylformamide (20 mL), was added methyl3-(bromomethyl)benzoate (0.90 g, 3.96 mmol). After stirring at 55° C.for 4 hours, the reaction mixture was diluted with ethyl acetate (100mL), washed with dilute citric acid, water and brine. The organic phasewas dried over MgSO₄, filtered and isolated by Biotage flashchromatography (10-100% ethyl acetate/hexanes) to obtain the titlecompound (1.2 g, 65%); ¹H NMR (DMSO-d₆): δ 1.39 (s, 9H), 1.68 (d, 2H,J=9.6 Hz), 1.80-1.88 (m, 2H), 3.43 (br, 2H), 3.68 (s, 3H), 3.76 (br,2H), 3.85 (s, 3H), 4.55 (s, 2H), 4.60 (s, 2H), 6.80-6.88 (m, 4H),7.49-7.59 (m, 2H), 7.89-7.90 (m, 2H); MS for C₂₈H₃₅N₃O₆ m/z 510.01(M+H)⁺.

Example 37 Compound 563-((1-(4-Methoxyphenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To a solution of methyl3-((1-(4-methoxyphenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.32 g, 0.55 mmol) in methanol (3 mL) was added lithium hydroxidemonohydrate (0.046 g, 1.1 mmol) in water (1 mL). After stirring at roomtemperature for 18 h, the reaction mixture was concentrated in vacuo andisolated by reverse phase HPLC to obtain the title compound as anacetate salt (0.15 g, 48%); ¹H NMR (DMSO-d₆): δ 1.64 (d, 2H, J=13.6 Hz),1.77 (t, 2H, J=6.4 Hz), 1.95-2.02 (m, 2H), 2.31 (t, 2H, J=6 Hz),2.57-2.67 (m, 4H), 3.68 (s, 3H), 3.79 (t, 2H, J=6.8 Hz), 4.34 (d, 4H,J=26.8 Hz), 6.84 (dd, 2H, J=4.8 and 2 Hz), 6.92-6.96 (m, 5H), 7.09-7.12(m, 1H), 7.49-7.52 (m, 2H), 7.86-7.87 (m, 2H), 10.77 (s, 1H), 12.95 (br,1H); MS for C₃₂H₃₅N₅O₅ m/z 570.04 (M+H)⁺.

Example 38 Compound 57 methyl3-((8-(3-(1H-indol-3-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of methyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (871mg, 2.11 mmol, 1.05 equiv), 3-(3-iodopropyl)-1H-indole (574 mg, 2.01mmol, 1 equiv), and potassium carbonate (833 mg, 6.03 mmol, 3 equiv) inN—N-dimethylformamide was heated at 65° C. for 16 h. The reaction wascooled to ambient temperature and worked up using ethyl acetate andwater. The organic layer was dried over MgSO₄, filtered and concentratedin vacuo. The crude residue was purified using preparatory thin layerchromatography in 7% methanol in dichloromethane to afford the titlecompound as cream crystals (252 mg, 46%); ¹H NMR (400 MHz, DMSO-d₆): δ1.62 (d, 2H, J=12 Hz), 1.84 (bs, 2H); 2.41 (bs, 2H); 2.57 (bs, 2H); 2.67(bs, 2H); 2.71-2.75 (m, 4H); 3.85 (s, 3H); 4.59 (s, 2H); 4.63 (s, 2H);6.77 (d, 1H, J=7.6 Hz); 6.85 (d, 2H, J=8 Hz); 6.96 (t, 1H, J=6.8 and 7.6Hz); 7.03-7.07 (m, 1H); 7.13 (bs, 1H); 7.22 (t, 2H, J=8 Hz); 7.33 (d,1H, J=8 Hz); 7.52-7.59 (m, 3H); 7.89-7.91 (m, 2H); 10.75 (s, 1H); MS forC₃₃H₃₆N₄O₃ m/z 537.06 (M+H)⁺.

Preparation of 3 (3-iodopropyl)-1H-indole

Sodium iodide (827 mg, 5.52 mmol, 2 equiv) was added to a solution of3-(1H-indol-3-yl)propyl 4-methylbenzenesulfonate (909 mg, 2.76 mmol, 1equiv) in acetone, and the mixture was refluxed for 16 h. Upon coolingthe reaction, it was evaporated under reduced pressure and the residuewas taken into dichloromethane. The organic layer was washed with water,dried over MgSO₄, filtered and concentrated in vacuo. The crude mixturewas purified using the Biotage flash chromatography system (SNAP 50 gcartridge, R_(f)=0.7, gradient—5%-30% ethyl acetate in hexanes) toafford the title compound as an oil (789 mg, quant); ¹H NMR (400 MHz,DMSO-d₆): δ 2.07-2.14 (m, 2H); 2.78 (t, 2H, J=7.6 and 6.8 Hz); 3.29 (t,2H, J=6.8 Hz); 6.95-6.99 (m, 1H); 7.04-7.08 (m, 1H); 7.14 (d, 1H, J=2Hz); 7.32-7.34 (m, 1H); 7.52 (d, 1H, J=8 Hz); 10.81 (s, 1H); MS forC₁₁H₁₂IN m/z 285.12 (M+H)⁺.

Example 39 Compound 583-((8-(3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of methyl3-((8-(3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(326 mg, 0.575 mmol, 1 equiv) and lithium hydroxide (48.3 mg, 1.15 mmol,2.0 equiv) in a 4:1 mixture of methanol and water (5 ml t/v) was stirredat 35° C. for 24 hrs. The reaction was concentrated in vacuo andpurified using preparatory high performance liquid chromatography. Thecombined pure fractions were lyophilized to afford the acetate salt ofthe title compound as a white solid (56 mg, 17%); ¹H NMR (400 MHz,DMSO-d₆): δ 1.61 (d, 2H, J=13.6 Hz), 1.84 (t, 2H, J=6.8 Hz); 2.37 (t,2H, J=7.2 Hz, J=6.4 Hz); 2.54-2.59 (m, 2H); 2.66-2.73 (m, 4H); 3.32 (s,3H); 3.91 (t, 2H, J=6.8 Hz); 4.58 (s, 2H); 4.60 (s, 2H); 6.76 (t, 1H,J=7.2 Hz); 6.85 (d, 2H, J=8 Hz); 7-7.07 (m, 2H); 7.12-7.15 (m, 1H);7.2-7.26 (m, 3H); 7.47-7.53 (m, 2H); 7.86-7.88 (m, 2H); 12.9 (bs, 1H);MS for C₃₂H₃₅N₅O₄ m/z 554.05 (M+H)⁺.

Example 40 Compound 593-((8-(3-(1H-indol-3-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of methyl methyl3-((8-(3-(1H-indol-3-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(350 mg, 0.651 mmol, 1 equiv) and lithium hydroxide (54.65 mg, 1.302mmol, 2.0 equiv) in a 4:1 mixture of methanol and water (5 ml t/v) wasstirred at 35° C. for 24 hrs. The reaction was concentrated in vacuo andpurified using preparatory high performance liquid chromatography. Thecombined pure fractions were lyophilized to afford the acetate salt ofthe title compound as a white solid (170 mg, 50%); ¹H NMR (400 MHz,DMSO-d₆): δ 1.63 (d, 2H, J=13.6 Hz), 1.86 (t, 2H, J=7.6 Hz, J=7.2 Hz);2.46 (bs, 2H); 2.59-2.62 (m, 2H); 2.71-2.85 (m, 4H); 4.59 (s, 2H); 4.61(s, 2H); 6.74 (t, 1H, J=7.2 Hz); 6.84 (d, 2H, J=8 Hz); 6.93-6.97 (m,1H); 7.03-7.07 (m, 1H); 7.13 (d, 1H, J=2.4 Hz); 7.18 (t, 2H, J=7.6 and8.4 Hz); 7.32 (d, 1H, J=8.4 Hz); 7.47-7.54 (m, 3H); 7.86-7.88 (m, 2H);10.74 (s, 1H); 12.6 (bs, 1H); MS for C₃₂H₃₄N₄O₃ m/z 523.07 (M+H)⁺.

Example 41 Compound 60 tert-Butyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (500mg, 1.19 mmol, 1 equiv),1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one-one (358.8 mg, 1.19mmol, 1 equiv), and potassium carbonate (493.4 mg, 3.57 mmol, 3 equiv)in N,N-dimethylformamide was heated at 65° C. for 16 h. After cooling toambient temperature, the crude mixture was partitioned between ethylacetate and water. The organic layer was dried over MgSO₄, filtered,concentrated, and the crude residue was purified using preparatory thinlayer chromatography in 10% methanol in dichloromethane to afford thetitle compound (548 mg, 77.4%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.52 (s,9H); 1.61 (d, 2H, J=12.8 Hz), 1.83 (t, 2H, J=6.8 Hz); 2.36 (t, 2H, J=6.8Hz); 2.54-2.73 (m, 6H); 3.86 (t, 2H, J=6.8 and 6.4 Hz); 4.58 (s, 2H);4.61 (s, 2H); 6.77 (t, 1H, J=7.6 and 7.2 Hz); 6.85 (d, 2H, J=8 Hz); 6.97(d, 1H, J=2.8 Hz); 7.18-7.25 (m, 3H); 7.48-7.55 (m, 2H); 7.79-7.84 (m,2H); 10.81 (s, 1H); MS for C₃₅H₄₁N₅O₄ m/z 596.16 (M+H)⁺.

Example 42 Compound 61 tert-butyl3-((8-(3-(3-(heptanoyloxymethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

tert-Butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.200 g, 0.474 mmol),(3-(3-chloropropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methylheptanoate (0.17 g, 0.474 mmol), sodium iodide (0.021 g, 0.142 mmol),and potassium carbonate (0.0983 g, 0.711 mmol) in 2-butanone (5 mL) wereheated at 78° C. for 4 hours. The reaction was diluted with 10%methanol/dichloromethane, filtered, and evaporated. The residue waspurified by PTLC (50% ethyl acetate/hexanes) to give product as foam(0.30 g, 86%); NMR (DMSO-d₆); δ0.78 (t, J=6.4 Hz, 3H); 1.16 (m, 6H);1.44-1.48 (m, 2H); 1.51 (s, 9H); 1.60 (m, 2H); 1.84-1.87 (m, 2H); 2.28(t, J=6.8 Hz, 2H); 2.35 (m, 2H); 2.51-2.59 (m, 2H); 2.65-2.71 (m, 4H);3.93 (t, J=6.8 Hz, 2H); 4.58 (s, 2H); 4.61 (s, 2H); 5.88 (s, 2H); 6.77(t, J=7.2 Hz, 1H); 6.85 (d, J=8 Hz, 2H); 7.06-7.10 (m, 2H); 7.22 (t,J=8.4 Hz, 2H); 7.26-7.32 (m, 2H); 7.48-7.54 (m, 2H); 7.79 (s, 1H);7.82-7.84 (m, 1H); MS for C₄₃H₅₅N₅O₆ m/z 738 (M+H)⁺.

Preparation of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A solution of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (10 g, 43.23mmol, 1 equiv) in dichloromethane was treated with pyridine (6.99 ml,86.46 mmol, 2 equiv) at 0° C. This was followed by the slow addition ofbenzyl chloroformate (6.39 ml, 45.4 mmol, 1.05 equiv). The reaction wasstirred at ambient temperature for 16 h. The mixture was partitionedbetween dichloromethane and 10% citric acid followed by washes withwater and brine. The combined organic layers were dried over MgSO₄,filtered and concentrated in vacuo to afford benzyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as anoff-white powder (12.5 g, 79%); MS for C₂₁H₂₃N₃O₃ m/z 366.18 (M+H)⁺.

A mixture of benzyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (12.5 g, 34.21mmol, 1 equiv), sodium bis(trimethylsilyl)amide, 1M in tetrahydrofuran(37.63 ml, 37.63 mmol, 1.1 equiv), and tert-butyl3-(bromomethyl)benzoate (9.27 g, 34.21 mmol, 1 equiv) inN,N-dimethylformamide was stirred for 16 h at ambient temperature.Reaction was diluted with ethyl acetate and the organic layer was washedwith water and brine. The combined organic layers were dried over MgSO₄and concentrated in vacuo. The crude residue was purified using theBiotage flash chromatography system (SNAP 100 g cartridge, R_(f)=0.6,10%-50% ethyl acetate in hexanes) to afford benzyl3-(3-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(19 g, quant) as a cream solid; ¹H NMR (400 MHz, DMSO-d₆): δ 1.53 (s,9H); 1.71 (d, 2H, J=13.6 Hz); 2.37-2.42 (m, 2H); 3.6 (bs, 2H); 4.01-4.03(m, 2H); 4.61 (s, 2H); 4.64 (s, 2H); 5.14 (d, 2H, J=7.2 Hz); 6.69 (d,2H, J=8 Hz); 6.79 (t, 2H, J=7.2 Hz); 7.16-7.2 (m, 2H); 7.32-7.39 (m,5H); 7.49-7.56 (m, 2H); 7.81-7.85 (m, 2H); MS for C₃₃H₃₇N₃O₅ m/z 556.28(M+H)⁺.

A solution of benzyl3-(3-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(5 g, 9.0 mmol, 1 equiv) in a mixture of ethyl acetate and ethanol wascharged with 10% palladium on carbon (1 g, 20%/wt) and the resultingmixture was stabilized to a hydrogen atmosphere. The reaction wasstirred as such for 2 h, filtered through Celite and the filtrate wasconcentrated in vacuo to afford the title compound as a grey foam (3.69g, 97%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.52 (s, 9H); 1.54-1.56 (m, 2H);2.43-2.49 (m, 2H); 2.88-2.93 (m, 2H); 3.18-3.24 (m, 2H); 4.58 (s, 2H);4.62 (s, 2H); 6.74 (t, 2H, J=6.8 and 7.6 Hz); 6.88 (d, 2H, J=8 Hz);7.18-7.22 (m, 2H); 7.49-7.55 (m, 2H); 7.79-7.85 (m, 2H); MS forC₂₅H₃₁N₃O₃ m/z 422.24 (M+H)⁺.

Preparation of(3-(3-chloropropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methylheptanoate

Heptanoyl chloride (0.64 mL, 4.15 mmol) was added dropwise at 0° C. to1-(3-chloropropyl)-3-(hydroxymethyl)-1H-benzo[d]imidazol-2(3H)-one (1.00g, 4.15 mmol) and pyridine (0.50 mL, 6.23 mmol) in dichloromethane (20mL) and then allowed to warm to room temperature. The mixture was washedwith water and brine, dried (MgSO₄), and evaporated. The residue waspurified by PTLC (30% ethyl acetate/hexanes) to give product as an oil(1.35 g, 92%); NMR (DMSO-d₆); δ0.80 (t, J=6.8 Hz, 3H); 1.15-1.19 (m,6H); 1.46-1.49 (m, 2H); 2.08-2.12 (m, 2H); 2.30 (t, J=7.2 Hz, 2H); 3.67(t, J=6.4 Hz, 2H); 3.97 (t, J=6.8 Hz, 2H); 5.88 (s, 2H); 7.10-7.16 (m,2H); 7.24-7.29 (m, 2H); MS for C₁₈H₂₅ClN₂O₃ m/z 353 (M+H)⁺.

Preparation of1-(3-chloropropyl)-3-(hydroxymethyl)-1H-benzo[d]imidazol-2(3H)-one

1-(3-Chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.30 g, 1.42mmol), paraformaldehyde (0.0853 g, 2.84 mmol), and sodium acetate (0.117g, 1.42 mmol) in acetic acid (3 mL) were heated at 65° C. for 20 hours.The mixture was evaporated to dryness, dissolved in ethyl acetate,washed with saturated aqueous sodium bicarbonate and brine, dried(MgSO₄), and evaporated. The residue was purified by PTLC (50% ethylacetate/hexanes) to give product as a white solid (0.31 g, 90%); NMR(DMSO-d₆); δ2.06-2.13 (m, 2H); 3.66 (t, J=6.4 Hz, 2H); 3.96 (t, J=6.8Hz, 2H); 5.22 (d, J=7.2 Hz, 2H); 6.38 (t, J=7.2 Hz, 1H); 7.07 (m, 2H);7.20-7.22 (m, 1H); 7.23-7.25 (m, 1H); MS for C₁₁H₁₃ClN₂O₂ m/z 241(M+H)⁺.

Example 43 Compound 62 tert-butyl3-((1-cyclohexyl-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

tert-Butyl3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.823 g, 1.92 mmol), 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one(0.58 g, 1.92 mmol), and potassium carbonate (0.39 g, 2.88 mmol) inN,N-dimethylformamide (8 mL) were heated at 65° C. for 2 hours. Thereaction was diluted with ethyl acetate, washed with water and brine,dried (MgSO₄), and evaporated. The residue was purified by PTLC (5%methanol/dichloromethane) to give product as a white solid (0.84 g,73%); ¹H NMR (DMSO-d₆); δ 0.93-0.96 (m, 1H); 1.14-1.25 (m, 4H); 1.52 (s,9H); 1.57-1.62 (m, 9H); 1.79 (m, 2H); 2.29-2.36 (m, 4H); 2.63 (m, 3H);3.82 (t, J=6.8 Hz, 2H); 4.08 (s, 2H); 4.43 (s, 2H); 6.97-7.01 (m, 3H);7.14 (d, J=6.4 Hz, 1H); 7.44-7.49 (m, 2H); 7.72 (s, 1H); 7.81 (dt, J=2.4Hz and 6.4 Hz, 1H); 10.8 (s, 1H); MS for C₃₅H₄₇N₅O₄ m/z 602 (M+H)⁺.

Preparation of tert-butyl3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

Benzyl3-(3-(tert-butoxycarbonyl)benzyl)-1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate(1.37 g, 2.44 mmol) and palladium on carbon (10 wt. %, wet, Degussa typeE101 NE/W,) (0.27 g) in ethyl acetate (20 mL) was stirred at roomtemperature under hydrogen (balloon) for 3 hours. The catalyst wasremoved by filtration and the filtrate evaporated and dried under vacuumto give product as a foam (1.04 g, quant.); MS for C₂₅H₃₇N₃O₃ m/z 428(M+H)⁺.

Preparation of benzyl3-(3-(tert-butoxycarbonyl)benzyl)-1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate

Sodium hydride (0.0699 g, 2.91 mol) was added portionwise at 0° C. tobenzyl 1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate(1.03 g, 2.77 mmol) in N,N-dimethylformamide (5 mL) and stirred at 0° C.for 10 minutes. tert-Butyl 3-(bromomethyl)benzoate (0.75 g, 2.77 mmol)was added dropwise at 0° C., the mixture allowed to warm to roomtemperature, and stirred overnight. The reaction was diluted with waterand extracted with ethyl acetate. The extracts were washed with waterand brine, dried (MgSO₄) and evaporated. The residue was purified byPTLC (50% ethyl acetate/hexanes) to give product as an oil (1.37 g,88%); ¹H NMR (DMSO-d₆); δ0.97 (m, 1H); 1.20 (m, 4H); 1.53 (s, 9H);1.53-1.69 (m, 9H); 2.60 (m, 1H); 3.59 (m, 2H); 3.73 (m, 2H); 4.47 (s,2H); 5.09 (s, 2H); 7.30-7.39 (m, 5H); 7.45-7.50 (m, 2H); 7.73 (m, 1H);7.81 (m, 1H); MS for C₃₃H₄₃N₃O₅ m/z 562 (M+H)⁺.

Preparation of benzyl1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate

Benzyl chloroformate (1.74 mL, 0.0116 mmol) was added dropwise at 0° C.to 1-cyclohexyl-1,3,8-triazaspiro[4.5]decan-4-one, hydrochloride(prepared as described in J. Med. Chem. 1998, 41, 5084-5093); ¹H NMR(DMSO-d₆); δ1.11 (m, 2H); 1.24 (m, 4H); 1.58 (m, 4H); 1.77 (m, 4H); 2.38(m, 2H); 3.32 (m, 3H); 4.21 (s, 2H); 9.35 (br s, 1H); 12.7 (br s, 1H);(3.59 g, 0.0116 mol) in pyridine (35 mL). The mixture was allowed towarm to room temperature and then evaporated. The residue was dilutedwith ethyl acetate, washed with water and brine, dried (MgSO₄) andevaporated. The residue was purified by Biotage flash chromatography (5%methanol/dichloromethane) to give product as a white solid (2.15 g,50%); ¹H NMR (DMSO-d₆); δ1.04 (m, 1H); 1.23-1.31 (m, 4H); 1.55-1.58 (m,6H); 1.67 (d, J=10.4 Hz, 2H); 2.52 (m, 2H); 3.51 (m, 2H); 3.74-3.77 (m,2H); 4.10 (s, 2H); 5.08 (s, 2H); 7.31-7.39 (m, 5H); 8.20 (br s, 1H).

Example 44 Compound 64 Benzyl3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-(benzyloxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(2.7 g, 4.86 mmol) was added 4M solution of HCl in dioxane (7 mL). Afterstirring at room temperature for an hour, the reaction mixture wasconcentrated in vacuo to obtain benzyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as ahydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (1.68 g,12.15 mmol) in N,N-dimethylformamide (20 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (1.47 g, 4.86 mmol).After stirring at 55° C. for 18 hours, the reaction mixture was dilutedwith ethyl acetate (100 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated byBiotage flash chromatography (2-20% methanol/dichloromethane) to obtainthe product (2.6 g, 88%); ¹H NMR (DMSO-d₆): δ 1.55 (d, 2H, J=13.2 Hz),1.82 (t, 2H, J=6.4 Hz), 2.33 (t, 2H, J=6.8 Hz), 2.50-2.59 (m, 6H), 3.85(t, 2H, J=6.8 Hz), 4.59 (d, 4H, J=16.8 Hz), 5.32 (s, 2H), 6.76 (t, 1H,J=7.2 Hz), 6.83 (d, 2H, J=8 Hz), 6.96 (d, 3H, J=1.2 Hz), 7.18-7.24 (m,3H), 7.31-7.36 (m, 3H), 7.42 (dd, 2H, J=7.6 and 1.6 Hz), 7.52-7.59 (m,2H), 7.86 (s, 1H), 7.91-7.94 (m, 1H), 10.83 (s, 1H); MS for C₃₈H₃₉N₅O₄m/z 630.14 (M+H)⁺.

Example 45 Compound 695-(4-Oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-5-phenylpentanoicacid

To a solution of methyl5-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-5-phenylpentanoate(0.13 g, 0.22 mmol) in methanol (3 mL) was added lithium hydroxidemonohydrate (0.018 g, 0.44 mmol) in water (1 mL). After stirring at roomtemperature for 24 h, the reaction mixture was concentrated in vacuo andisolated by reverse phase HPLC to obtain the title compound as anacetate salt (0.075 g, 56%); ¹H NMR (DMSO-d₆): δ 1.41-1.58 (m, 4H), 1.81(t, 2H, J=6.8 Hz), 1.97-2.11 (m, 2H), 2.26-2.35 (m, 4H), 2.49-2.53 (m,2H), 2.61-2.67 (m, 5H), 3.84 (t, 2H, J=6.8 Hz), 4.26 (d, 1H, J=5.6 Hz),4.74 (d, 1H, J=5.6 Hz), 5.15-5.19 (m, 1H), 6.76 (t, 1H, J=6.8 Hz), 6.86(d, 2H, J=8 Hz), 6.96 (d, 3H, J=3.6 Hz), 7.17-7.24 (m, 3H), 7.29-7.32(m, 1H), 7.35-7.38 (m, 3H), 10.80 (s, 1H), 12.07 (br, 1H); MS forC₃₄H₃₉N₅O₄ m/z 582.12 (M+H)⁺.

Example 46 Compound 703-(4-Oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-3-phenylpropanoicacid

To a solution of methyl3-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-3-phenylpropanoate(0.22 g, 0.39 mmol) in methanol (3 mL) was added lithium hydroxidemonohydrate (0.033 g, 0.78 mmol) in water (1 mL). After stirring at roomtemperature for 24 h, the reaction mixture was concentrated in vacuo andisolated by reverse phase HPLC to obtain the title compound as anacetate salt (0.080 g, 37%); ¹H NMR (DMSO-d₆): δ 1.45 (d, 1H, J=13.2Hz), 1.55 (d, 1H, J=13.2 Hz), 1.81 (t, 2H, J=6.8 Hz), 2.33 (t, 2H, J=6.8Hz), 2.48-2.50 (m, 2H), 2.57-2.68 (m, 4H), 3.07-3.10 (m, 2H), 3.84 (t,2H, J=6.8 Hz), 4.37 (d, 1H, J=5.2 Hz), 4.70 (d, 1H, J=5.2 Hz), 5.52 (t,1H, J=7.2 Hz), 6.75 (t, 1H, J=7.2 Hz), 6.86 (d, 2H, J=8.4 Hz), 6.96 (d,3H, J=3.2 Hz), 7.16-7.24 (m, 3H), 7.29-7.32 (m, 1H), 7.37 (d, 4H, J=4Hz), 10.80 (s, 1H), 11.50 (br, 1H); MS for C₃₂H₃₅N₅O₄ m/z 554.05 (M+H)⁺.

Example 47 Compound 713-((4-Oxo-8-(3-(3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl3-((4-oxo-8-(3-(3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.1 g, 0.16 mmol) was added 4M solution of HCl in dioxane (2 mL). Afterstirring at room temperature for 3 hours, the reaction mixture wasconcentrated in vacuo and lyophilized in acetonitrile/water (1:1) toobtain the title compound as a hydrochloride salt (0.095 g, 99%); ¹H NMR(DMSO-d₆): δ 1.92 (d, 2H, J=14 Hz), 2.03-2.07 (m, 2H), 2.85 (t, 2H, J=10Hz), 3.25 (br, 2H), 3.62-3.72 (m, 4H), 3.99 (t, 2H, J=6.8 Hz), 4.61-4.67(m, 6H), 6.81 (t, 1H, J=7.6 Hz), 6.96-7.10 (m, 5H), 7.23 (t, 2H, J=7.2Hz), 7.31 (d, 1H, J=7.6 Hz), 7.48-7.57 (m, 2H), 7.87-7.89 (m, 2H), 9.96(br, 1H), 13.03 (s, 1H); MS for C₃₂H₃₄N₄O₅ m/z 555.06 (M+H)⁺.

Preparation of tert-butyl3-((4-oxo-8-(3-(3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2g, 0.47 mmol), potassium carbonate (0.097 g, 0.7 mmol) and sodium iodide(0.021 g, 0.14 mmol) in 2-butanone (5 mL), was added4-(3-chloropropyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (0.107 g, 0.47mmol). After stirring at 78° C. for 18 hours, the reaction mixture wasfiltered, concentrated and isolated by preparatory TLC (10%methanol/dichloromethane) to obtain the title compound (0.1 g, 35%); ¹HNMR (DMSO-d₆): δ 1.52 (s, 9H), 1.62 (d, 2H, J=12.8 Hz), 1.75 (t, 2H,J=6.8 Hz), 2.40 (t, 2H, J=7.2 Hz), 2.45-2.62 (m, 2H), 2.66-2.73 (m, 4H),3.99 (t, 2H, J=7.2 Hz), 4.58-4.63 (m, 6H), 6.76 (t, 1H, J=7.2 Hz), 6.85(d, 2H, J=8.4 Hz), 7.00 (m, 3H), 7.21 (t, 2H, J=7.2 Hz), 7.33-7.34 (m,1H), 7.48-7.55 (m, 2H), 7.79 (s, 1H), 7.83 (d, 1H, J=7.2 Hz); MS forC₃₆H₄₂N₄O₅ m/z 611.12 (M+H)⁺.

Preparation of 4-(3-chloropropyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

To a solution of 2H-1,4-benzoxazin-3(4H)-one (1.0 g, 6.7 mmol) andpotassium carbonate (1.4 g, 10.05 mmol) in N,N-dimethylformamide (20mL), was added 1-bromo-3-chloropropane (1.99 mL, 20.1 mmol, d=1.6).After stirring at 60° C. for 60 hours, the reaction mixture was dilutedwith ethyl acetate (100 mL), washed with dilute citric acid, water andbrine. The organic phase was dried over MgSO₄ and concentrated to thetitle compound (1.46 g, 97%); ¹H NMR (DMSO-d₆): δ 1.99-2.03 (m, 2H),3.71 (t, 2H, J=6.4 Hz), 4.00-4.04 (m, 2H), 4.63 (s, 2H), 7.00-7.01 (m,2H), 7.03-7.09 (m, 1H), 7.22 (d, 1H, J=7.6 Hz); MS for C₁₁H₁₂ClNO₂ m/z225.96 (M+H)⁺.

Example 48 Compound 723-((1-cyclohexyl-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, formate

tert-Butyl3-((1-cyclohexyl-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.3 g, 0.534 mmol), and formic acid (8 mL) were stirred at roomtemperature for 20 hours. The reaction was evaporated to dryness and theresidue purified by PTLC (10% methanol/dichloromethane). The product wasdissolved in formic acid (5 mL) and then evaporated under vacuum. Theresidue was dissolved in acetonitrile (5 mL) and water (5 mL) andlyophilized to give product as a white solid (0.24 g, 75%); HPLC rt 9.24min; ¹H NMR (DMSO-d₆); δ0.85-1.00 (m, 1H); 1.12-1.22 (m, 4H); 1.49-1.52(m, 2H); 1.61-1.72 (m, 6H); 1.84 (t, J=6.4 Hz, 2H); 2.46 (t, J=6.8 Hz,2H); 2.52-2.56 (m, 4H); 2.79 (t, J=8.4 Hz, 2H); 3.82 (t, J=6.4 Hz, 2H);4.08 (s, 2H); 4.43 (s, 2H); 6.96-7.00 (m, 3H); 7.14-7.15 (m, 1H);7.41-7.46 (m, 2H); 7.81-7.83 (m, 2H); 8.17 (br s, 1H); 10.8 (s, 1H); MSfor C₃₁H₃₉N₅O₄ m/z 546 (M+H)⁺.

Example 49 Compound 743-((8-(heptanoyloxymethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, formate

tert-Butyl3-((8-(3-(3-(heptanoyloxymethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.30 g, 0.407 mmol) and formic acid (8 mL) were stirred at roomtemperature for 20 hours. The reaction was evaporated to dryness and theresidue purified by PTLC (10% methanol/dichloromethane). The product wasdissolved in formic acid (5 mL) and then evaporated under vacuum. Theresidue was dissolved in acetonitrile (5 mL) and water (5 mL) andlyophilized to give product as a white solid (0.14 g, 60%); NMR(DMSO-d₆); δ0.78 (t, J=6.8 Hz, 3H); 1.16-1.18 (m, 6H); 1.43-1.48 (m,2H); 1.65 (d, J=13.6 Hz, 2H); 1.90 (m, 2H); 2.29 (t, J=7.6 Hz, 2H);2.49-2.63 (m, 4H); 2.86 (m, 4H); 3.93 (t, J=6.8 Hz, 2H); 4.59 (s, 2H);4.61 (s, 2H); 5.88 (s, 2H); 5.88 (s, 2H); 6.76 (t, J=7.6 Hz, 1H); 7.86(d, J=8.4 Hz, 2H); 7.06-7.12 (m, 2H); 7.20 (m, 2H); 7.26-7.32 (m, 2H);7.48-7.54 (m, 2H); 7.87 (m, 2H); 8.15 (s, 1H); MS for C₂₉H₃₇N₃O₅ m/z 508(M+H)⁺.

Example 50 Compound 763-((8-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl3-((8-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.17 g, 0.3 mmol) was added 4M solution of HCl in dioxane (3 mL). Afterstirring at room temperature for 4 hours, the reaction mixture wasconcentrated in vacuo and lyophilized in acetonitrile/water (1:1) toobtain the title compound as a hydrochloride salt (0.16 g, 99%); ¹H NMR(DMSO-d₆): δ 1.96 (d, 2H, J=14 Hz), 2.91-3.02 (m, 2H), 3.45-3.71 (m,6H), 4.03-4.08 (m, 1H), 4.36 (d, 1H, J=9.2 Hz), 4.61-4.66 (m, 4H), 4.92(br, 1H), 6.81-6.97 (m, 5H), 7.04 (d, 2H, J=8 Hz), 7.24 (t, 2H, J=8.4Hz), 7.49-7.59 (m, 2H), 8.89 (d, 2H, J=8.8 Hz), 10.83 (br, 1H), 13.04(br, 1H); MS for C₃₀H₃₁N₃O₅ m/z 513.99 (M+H)⁺.

Preparation of tert-butyl3-((8-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.23 g, 0.55 mmol) and potassium carbonate (0.114 g, 0.83 mmol) inN,N-dimethylformamide (5 mL), was added2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine (0.082 mL, 0.55 mmol,d=1.533). After stirring at 55° C. for 18 hours, the reaction mixturewas filtered, concentrated and isolated by preparatory TLC (7%methanol/dichloromethane) to obtain the title compound (0.17 g, 54%); ¹HNMR (DMSO-d₆): δ 1.52 (s, 9H), 1.63 (d, 2H, J=12 Hz), 2.54-2.60 (m, 2H),2.65 (d, 2H, J=6 Hz), 2.81-2.93 (m, 6H), 3.99-4.04 (m, 1H), 4.37 (dt,2H, J=10.4 and 2.4 Hz), 4.60 (d, 2H, J=11.2 Hz), 6.76-6.88 (m, 7H), 7.23(t, 2H, J=8.8 Hz), 7.48-7.55 (m, 2H), 7.79 (m, 1H), 7.83 (dt, 1H, J=7.2and 2 Hz); MS for C₃₄H₃₉N₃O₅ m/z 570.12 (M+H)⁺.

Example 51 Compound 773-((8-(4,4-(4-fluorophenyl)butyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of tert-butyl3-((8-(4,4-bis(4-fluorophenyl)butyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(400 mg, 0.601 mmol, 1 equiv) in 4M solution hydrogen chloride indioxane was stirred at ambient temperature for 3 h. The mixture wasconcentrated in vacuo and the crude residue was purified usingpreparatory high performance liquid chromatography to afford the acetatesalt of the title compound as a white solid (203 mg, 56%); ¹H NMR (400MHz, DMSO-d₆): δ 1.45 (bs, 2H); 1.71 (d, 2H, J=12.8 Hz); 2.01-2.07 (m,2H); 2.67 (bs, 4H); 3.32 (bs, 4H); 4.03 (t, 1H, J=8 Hz); 4.59 (s, 2H);4.61 (s, 2H); 6.76 (t, 1H, J=6.4 and 7.2 Hz); 6.86 (d, 2H, J=8 Hz); 7.11(t, 4H, J=9.2 and 8.4 Hz); 7.18 (t, 2H, J=7.2 and 8.4 Hz); 7.33-7.36 (m,4H); 7.48-7.55 (m, 2H); 7.87-7.89 (m, 2H); MS for C₃₇H₃₇F₂N₃O₃ m/z610.18 (M+H)⁺.

Preparation of tert-butyl3-((8-(4,4-bis(4-fluorophenyl)butyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methylbenzoate

A mixture of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (400mg, 0.949 mmol, 1 equiv),4,4′-(4-chlorobutane-1,1-diyl)bis(fluorobenzene) (222.06 μl, 0.949 mmol,1 equiv), potassium carbonate (393.5 mg, 2.847 mmol, 3 equiv), andsodium iodide (42.7 mg, 0.285 mmol, 0.3 equiv) in 2-butanone was stirredat 81° C. for 16 h. After cooling, the reaction mixture was filtered,filtrate concentrated, and the crude residue was purified using theBiotage flash chromatography system (SNAP 50 g cartridge, R_(f)=0.5,gradient—1%-10% methanol in dichloromethane) to afford the titlecompound as a white crystalline solid (500 mg, 80.8%); ¹H NMR (400 MHz,DMSO-d₆): δ 1.35 (bs, 2H); 1.51 (s, 9H); 1.59 (d, 2H, J=13.2 Hz);2.02-2.04 (m, 2H); 2.36 (bs, 2H); 2.52-2.53 (m, 2H); 2.64-2.67 (m, 4H);4.11 (s, 1H); 4.57 (s, 2H); 4.60 (s, 2H); 6.75 (bs, 1H); 6.81 (d, 2H,J=8.4 Hz); 7.08-7.12 (m, 4H); 7.16-7.20 (m, 2H); 7.32-7.36 (m, 4H);7.49-7.53 (m, 2H); 7.78 (bs, 1H); 7.82-7.84 (m, 1H); MS for C₄₁H₄₅F₂N₃O₃m/z 666.18 (M+H)⁺.

Example 52 Compound 823-((1-(4-Methoxyphenyl)-4-oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To a solution of methyl3-((1-(4-methoxyphenyl)-4-oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.19 g, 0.32 mmol) in methanol (3 mL) was added lithium hydroxidemonohydrate (0.027 g, 0.63 mmol) in water (1 mL). After stirring at roomtemperature for 18 h, the reaction mixture was concentrated in vacuo andisolated by preparatory TLC (10% methanol/dichloromethane) to obtain thetitle compound (0.11 g, 59%); ¹H NMR (DMSO-d₆): δ 1.64 (d, 2H, J=13.6Hz), 1.79 (t, 2H, J=6.4 Hz), 1.88-1.95 (m, 2H), 2.38 (t, 2H, J=6 Hz),2.50-2.66 (m, 4H), 3.69 (s, 3H), 3.97 (t, 2H, J=6.4 Hz), 4.53 (d, 4H,J=26.8 Hz), 6.86 (d, 2H, J=7.2 Hz), 6.94 (d, 2H, J=7.6 Hz), 7.16 (t, 1H,J=7.2 Hz), 7.30 (t, 1H, J=7.6 Hz), 7.38 (d, 1H, J=7.6 Hz), 7.47-7.53 (m,2H), 7.58 (dd, 1H, J=8 and 1.2 Hz), 7.85-8.87 (m, 2H), 12.95 (br, 1H);MS for C₃₂H₃₄N₄O₅S m/z 587.02 (M+H)⁺.

Preparation of methyl3-((1-(4-methoxyphenyl)-4-oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To tert-butyl3-(3-(methoxycarbonyl)benzyl)-1-(4-methoxyphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.26 g, 0.51 mmol) was added 4M solution of HCl in dioxane (5 mL).After stirring at room temperature for 3 hours, the reaction mixture wasconcentrated in vacuo to obtain methyl3-((1-(4-methoxyphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoateas a hydrochloride salt.

To a solution of the hydrochloride salt and potassium carbonate (0.176g, 1.28 mmol) in N,N-dimethylformamide (5 mL), was added3-(3-iodopropyl)benzo[d]thiazol-2(3H)-one (0.163 g, 0.51 mmol). Afterstirring at 55° C. for 18 hours, the reaction mixture was diluted withethyl acetate (25 mL), washed with water and brine. The organic phasewas dried over MgSO₄, filtered, concentrated and isolated by pTLC (10%methanol/dichloromethane) to obtain the product (0.2 g, 65%); ¹H NMR(DMSO-d₆): δ 1.62 (d, 2H, J=12.8 Hz), 1.77 (t, 2H, J=6.4 Hz), 1.89-1.92(m, 2H), 2.33 (t, 2H, J=6.4 Hz), 2.52-2.66 (m, 4H), 3.69 (s, 3H), 3.85(s, 3H), 3.97 (t, 2H, J=6.8 Hz), 4.49 (s, 2H), 4.57 (m, 2H), 6.87 (d,2H, J=8 Hz), 6.94 (d, 2H, J=7.6 Hz), 7.16 (t, 1H, J=8 Hz), 7.29 (t, 1H,J=7.6 Hz), 7.37 (d, 1H, J=7.6 Hz), 7.50-7.58 (m, 3H), 7.87-7.90 (m, 2H);MS for C₃₃H₃₆N₄O₅S m/z 601.04 (M+H)⁺.

Example 53 Compound 823-((8-(3-(1H-Indazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl3-((8-(3-(1H-indazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.16 g, 0.27 mmol) was added 4M solution of HCl in dioxane (2.5 mL).After stirring at room temperature for 3 hours, the reaction mixture wasconcentrated in vacuo and lyophilized in acetonitrile/water (1:1) toobtain the title compound as a hydrochloride salt (0.12 g, 79%); ¹H NMR(DMSO-d₆): δ 1.97 (d, 2H, J=14.4 Hz), 2.32-2.36 (m, 2H), 2.92-2.98 (m,2H), 3.19 (br, 2H), 3.45-3.70 (m, 4H), 4.54 (t, 2H, J=6.8 Hz), 4.63 (s,4H), 6.79 (t, 1H, J=7.6 Hz), 7.02 (d, 2H, J=8.4 Hz), 7.14-7.22 (m, 3H),7.42 (t, 1H, J=6.8 Hz), 7.48-7.57 (m, 2H), 7.73-7.79 (m, 2H), 7.87-7.88(m, 2H), 8.11 (s, 1H), 10.65 (br, 1H), 13.03 (br, 1H); MS for C₃₁H₃₃N₅O₃m/z 524.06 (M+H)⁺.

Preparation of tert-butyl3-((8-(3-(1H-indazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methylbenzoate

To a solution of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.14 g, 0.33 mmol), potassium carbonate (0.068 g, 0.5 mmol) and sodiumiodide (0.015 g, 0.01 mmol) in 2-butanone (3 mL), was added1-(3-chloropropyl)-1H-indazole (0.065 g, 0.33 mmol). After stirring at78° C. for 18 hours, the reaction mixture was filtered, concentrated andisolated by preparatory TLC (10% methanol/dichloromethane) to obtain thetitle compound (0.16 g, 84%); ¹H NMR (DMSO-d₆): δ 1.51 (s, 9H), 1.59 (d,2H, J=12.8 Hz), 2.03 (t, 2H, J=6.4 Hz), 2.24 (t, 2H, J=7.2 Hz),2.57-2.67 (m, 4H), 3.56 (t, 2H, J=6.4 Hz), 4.47-4.63 (m, 6H), 6.78 (t,1H, J=7.2 Hz), 6.85-6.87 (m, 2H), 7.11 (t, 1H, J=8 Hz), 7.24 (t, 2H, J=8Hz), 7.34 (t, 1H, J=7.6 Hz), 7.48-7.51 (m, 2H), 7.70-7.83 (m, 4H), 8.07(s, 1H); MS for C₃₅H₄₁N₅O₃ m/z 580.14 (M+H)⁺.

Preparation of 1-(3-chloropropyl)-1H-indazole

To a cooled (0° C.) solution of indazole (1.0 g, 8.46 mmol) inN,N-dimethylformamide (9 mL), was added 1M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (9.3 mL, 9.3 mmol), followedby addition of 1-bromo-3-chloropropane (2.5 mL, 25.4 mmol, d=1.6). Afterstirring at room temperature for 18 hours, the reaction mixture wasdiluted with ethyl acetate (100 mL), washed with saturated NH₄Cl, waterand brine. The organic phase was dried over MgSO₄, filtered and isolatedby Biotage flash chromatography (10-60% ethyl acetate/hexanes) thefractions with Rf=0.83 (1:1 ethyl acetate/hexanes) to obtain the titlecompound (1.03 g, 63%); ¹H NMR (DMSO-d₆): δ 2.23-2.30 (m, 2H), 3.58 (t,2H, J=6.4 Hz), 4.52 (t, 2H, J=6.4 Hz), 7.14 (t, 1H, J=7.2 Hz), 7.39 (t,1H, J=7.6 Hz), 7.66 (dd, 1H, J=8 and 0.8 Hz), 7.76 (dt, 1H, J=8 and 0.8Hz), 8.08 (s, 1H); MS for C₁₀H₁₁ClN₂ m/z 195.00 (M+H)⁺.

Example 54 Compound 83 methyl3-((1-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-phenyl-2,8-diazaspiro[4.5]decan-2-yl)methyl)benzoate

A mixture of methyl3-((1-oxo-4-phenyl-2,8-diazaspiro[4.5]decan-2-yl)methyl)benzoate (500mg, 1.206 mmol, 1 equiv),1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one-one (364.4 mg, 1.206mmol, 1 equiv), and potassium carbonate (500 mg, 3.62 mmol, 3 equiv) inN,N-dimethylformamide was stirred at 65° C. for 16 h. After cooling thereaction mixture, the crude mixture was partitioned between ethylacetate and water. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified using the Biotage flashchromatography system (SNAP 50 g cartridge, R_(f)=0.4, gradient—10%methanol in dichloromethane) to afford the title compound as a whitesolid (416 mg, 62%); ¹H NMR (400 MHz, DMSO-d₆): δ 0.99 (bs, 1H);1.57-1.59 (m, 2H); 1.67-1.74 (m, 3H); 1.86 (bs, 1H); 2.22-2.39 (m, 4H);2.73-2.76 (m, 2H); 3.25-3.27 (m, 1H); 3.59-3.62 (m, 1H); 3.76 (t, 2H,J=6.8 Hz); 3.86 (s, 3H); 4.55 (s, 2H); 6.94-6.95 (m, 3H); 7.09-7.11 (m,3H); 7.20-7.24 (m, 3H); 7.51-7.58 (m, 2H); 7.88-7.90 (m, 2H); 10.77 (s,1H); MS for C₃₃H₃₆N₄O₄ m/z 553.11 (M+H)⁺.

Preparation of methyl3-((1-oxo-4-phenyl-2,8-diazaspiro[4.5]decan-2-yl)methyl)benzoate

A solution of benzyl2-(3-(methoxycarbonyl)benzyl)-1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-carboxylate(1.335 g, 2.79 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 3 h. The mixture wasconcentrated in vacuo to afford the hydrogen chloride salt of the titlecompound as a cream powder (1.116 g, 97%); ¹H NMR (400 MHz, DMSO-d₆): δ1.11-1.18 (m, 1H); 1.71-1.83 (m, 2H); 1.93-1.97 (m, 1H); 3.38-3.42 (m,1H); 3.45-3.49 (m, 3H); 3.55-3.59 (m, 2H); 3.65-3.72 (m, 1H); 3.69-3.71(m, 1H); 3.86 (s, 3H); 4.57 (d, 2H, J=4 Hz); 7.19-7.21 (m, 2H);7.25-7.33 (m, 3H); 7.53-7.60 (m, 2H); 7.89-7.92 (m, 2H); 8.61 (bs, 1H);9.07 (bs, 1H); MS for C₂₃H₂₆N₂O₃ m/z 379.2 (M+H)⁺.

Preparation of benzyl2-(3-(methoxycarbonyl)benzyl)-1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-carboxylate

A mixture of benzyl1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-carboxylate (1 g, 3.03 mmol,1 equiv), lithium bis(trimethylsilyl)amide, 1M in tetrahydrofuran (3.33ml, 3.33 mmol, 1.1 equiv), and methyl 3-(bromomethyl)benzoate (694.08 g,3.03 mmol, 1 equiv) in N,N-dimethylformamide was stirred for 16 h atambient temperature. Reaction was diluted with ethyl acetate and theorganic layer was washed with water and brine. The combined organiclayers were dried over MgSO₄ and concentrated in vacuo. The cruderesidue was purified using the Biotage flash chromatography system (SNAP100 g cartridge, R_(f)=0.6, gradient—10%-50% ethyl acetate in hexanes)to afford the title compound as a cream solid (1.34 g, 92%); ¹H NMR (400MHz, DMSO-d₆): δ 0.87-0.92 (m, 1H); 1.33 (s, 9H); 1.46-1.51 (m, 2H);1.54-1.65 (m, 1H); 3.03-3.07 (m, ¹H); 3.34-3.40 (m, 3H); 3.46-3.48 (m,1H); 3.57-3.61 (m, 1H); 3.69-3.71 (m, 1H); 3.86 (s, 3H); 4.56 (s, 2H);7.14-7.16 (m, 2H); 7.20-7.28 (m, 3H); 7.52-7.59 (m, 2H); 7.89-7.91 (m,2H); MS for C₃₁H₃₂N₂O₅ m/z 513.23 (M+H)⁺.

Example 55 Compound 853-((8-(3-(1H-Benzo[d][1,2,3]triazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl3-((8-(3-(1H-benzo[d][1,2,3]triazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.21 g, 0.34 mmol) was added 4M solution of HCl in dioxane (3 mL).After stirring at room temperature for 3 hours, the reaction mixture wasconcentrated in vacuo and lyophilized in acetonitrile/water (1:1) toobtain the title compound as a hydrochloride salt (0.2 g, 99%); ¹H NMR(DMSO-d₆): δ 1.89 (d, 2H, J=14.8 Hz), 2.49-2.51 (m, 2H), 2.95-3.03 (m,2H), 3.22-3.27 (m, 2H), 3.53-3.69 (m, 4H), 4.64 (d, 4H, J=4 Hz), 4.86(t, 2H, J=7.2 Hz), 6.78 (t, 1H, J=7.2 Hz), 7.04 (d, 2H, J=8 Hz), 7.20(t, 2H, J=7.2 Hz), 7.41-7.61 (m, 4H), 7.86-7.89 (m, 2H), 7.97 (d, 1H,J=8.4 Hz), 8.07 (d, 1H, J=8.8 Hz), 10.94 (br, 1H), 13.03 (br, 1H); MSfor C₃₀H₃₂N₆O₃ m/z 525.08 (M+H)⁺.

Preparation of tert-butyl3-((8-(3-(1H-benzo[d][1,2,3]triazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2g, 0.47 mmol), potassium carbonate (0.097 g, 0.7 mmol) and sodium iodide(0.021 g, 0.14 mmol) in 2-butanone (5 mL), was added1-(3-chloropropyl)-1H-benzo[d][1,2,3]triazole (0.093 g, 0.47 mmol).After stirring at 78° C. for 18 hours, the reaction mixture wasfiltered, concentrated and isolated by preparatory TLC (10%methanol/dichloromethane) to obtain the title compound (0.21 g, 77%); ¹HNMR (DMSO-d₆): δ 1.51 (s, 9H), 1.58 (d, 2H, J=13.2 Hz), 2.13 (t, 2H,J=6.4 Hz), 2.30 (t, 2H, J=6.4 Hz), 2.49-2.53 (m, 2H), 2.66 (d, 4H, J=7.6Hz), 4.58 (d, 4H, J=9.6 Hz), 4.80 (t, 2H, J=6.4 Hz), 6.78 (t, 1H, J=6.8Hz), 6.84 (d, 2H, J=8 Hz), 7.25 (t, 2H, J=8 Hz), 7.39 (t, 1H, J=7.2 Hz),7.47-7.54 (m, 3H), 7.78 (s, 1H), 7.82 (dt, 1H, J=6.8 and 2 Hz), 7.93 (d,1H, J=8.4 Hz), 8.03 (d, 1H, J=8.4 Hz); MS for C₃₄H₄₀N₆O₃ m/z 581.20(M+H)⁺.

Preparation of 1-(3-chloropropyl)-1H-benzo[d][1,2,3]triazole

To a cooled (0° C.) solution of benzotriazole (1.0 g, 8.4 mmol) inN,N-dimethylformamide (10 mL), was added 1M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (12.6 mL, 12.6 mmol),followed by addition of 1-bromo-3-chloropropane (2.48 mL, 25.2 mmol,d=1.6). After stirring at room temperature for 18 hours, the reactionmixture was diluted with ethyl acetate (100 mL), washed with saturatedNH₄Cl, water and brine. The organic phase was dried over MgSO₄, filteredand isolated by Biotage flash chromatography (10-75% ethylacetate/hexanes) the fractions with Rf=0.66 (1:1 ethyl acetate/hexanes)to obtain the title compound (0.55 g, 33%); ¹H NMR (DMSO-d₆): δ2.34-2.41 (m, 2H), 3.64 (t, 2H, J=6.4 Hz), 4.84 (t, 2H, J=6.4 Hz), 7.41(t, 1H, J=7.2 Hz), 7.57 (t, 1H, J=7.2 Hz), 7.88 (dd, 1H, J=8.4 and 1.2Hz), 8.05 (dd, 1H, J=8.4 and 1.2 Hz); MS for C₉H₁₀ClN₃ m/z 196.01(M+H)⁺.

Example 56 Compound 893-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, hydrochloride

tert-Butyl3-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.15 g, 0.252 mmol) and 4M hydrochloric acid in 1,4-dioxane/1%triethylsilane (8 mL) were stirred at room temperature for 4 hours. Thereaction was evaporated and the residue purified by PTLC (10%methanol/dichloromethane) to give product as the formate salt; NMR(DMSO-d₆); δ1.67 (d, J=13.6 Hz, 2H); 1.82 (t, J=7.2 Hz, 2H); 2.57 (m,4H); 2.91 (m, 4H); 3.55 (s, 2H); 3.74 (t, J=6.8 Hz, 2H); 4.60 (s, 2H);4.61 (s, 2H); 6.77 (t, J=7.6 Hz, 1H); 6.86 (d, J=8 Hz, 2H); 6.99 (t, J=8Hz, 1H); 7.08 (d, J=7.6 Hz, 1H); 7.19-7.27 (m, 4H); 7.48-7.55 (m, 2H);7.87-7.88 (m, 2H); 8.14 (s, 1H). The formate salt was redissolved in 4Mhydrochloric acid in dioxane and evaporated. The residue was dissolvedin acetonitrile (5 mL) and water (5 mL) and lyophilized to give productas a white solid (0.10 g, 70%); HPLC rt 9.83 min; NMR (DMSO-d₆); δ1.90(d, J=14 Hz, 2H); 2.08 (m, 2H); 2.94 (m, 2H); 3.20 (m, 2H); 3.43 (m,2H); 3.50-3.64 (s, 2H); 3.57 (s, 3H); 3.77 (t, J=7.2 Hz, 2H); 4.64 (s,2H); 4.65 (s, 2H); 6.80 (t, J=7.2 Hz, 1H); 7.01-7.04 (m, 3H); 7.13 (d,J=8 Hz, 1H); 7.21 (t, J=8.8 Hz, 2H); 7.28 (m, 2H); 7.51 (t, J=8 Hz, 1H);7.56-7.57 (m, 1H); 7.87-7.89 (m, 2H); 10.7 (br s, 1H); 13.0 (br s, 1H);MS for C₃₂H₃₄N₄O₄ m/z 539 (M+H)⁺.

Preparation of tert-butyl3-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methylbenzoate

tert-Butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.30 g, 0.712 mmol), 1-(3-chloropropyl)indolin-2-one (0.15 g, 0.712mmol), sodium iodide (0.032 g, 0.214 mmol), and potassium carbonate(0.15 g, 1.07 mmol) in 2-butanone (8 mL) were heated at 78° C. for 4hours. The reaction was diluted with 10% methanol/dichloromethane,filtered, and evaporated. The residue was purified by PTLC (5%methanol/dichloromethane) to give product as an oil (0.15 g, 35%); NMR(DMSO-d₆); δ1.52 (s, 9H); 1.55-1.70 (m, 2H); 1.70-1.83 (m, 2H);2.33-2.45 (m, 2H); 2.51-2.63 (m, 2H); 2.63-2.80 (m, 4H); 3.55 (s, 2H);3.74 (t, J=6.8 Hz, 2H); 4.59 (s, 2H); 4.61 (s, 2H); 6.78 (t, J=7.2 Hz,1H); 6.86 (d, J=8 Hz, 2H); 6.99 (t, J=7.6 Hz, 1H); 7.09 (d, J=8 Hz, 1H);7.21-7.27 (m, 4H); 7.48-7.55 (m, 2H); 7.79 (s, 1H); 7.82-7.85 (m, 1H);MS for C₃₆H₄₂N₄O₄ m/z 595 (M+H)⁺.

Preparation of 1-(3-chloropropyl)indolin-2-one

Oxindole (2.00 g, 0.0150 mol), 1-bromo-3-chloropropane (2.97 mL, 0.03mol), and potassium carbonate (4.15 g, 0.03 mol) in acetonitrile (40 mL)were heated at reflux for 20 hours. The mixture was evaporated, dilutedwith ethyl acetate, washed with 2M aqueous hydrochloric acid and brine,dried (MgSO₄), and evaporated. The residue was purified by Biotage flashcolumn chromatography (30% ethyl acetate/hexanes) to give product as anoil which solidified on standing (1.57 g, 50%); MS for C₁₁H₁₂ClNO m/z210 (M+H)⁺.

Example 57 Compound 913-((8-(4-(4-methoxyphenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of tert-butyl3-((8-(4-(4-methoxyphenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(100 mg, 0.496 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 4 h. The mixture wasconcentrated in vacuo and the crude residue was purified usingpreparatory high performance liquid chromatography to afford the acetatesalt of the title compound as a white solid (67 mg, 74%); ¹H NMR (400MHz, DMSO-d₆): δ 1.78 (bs, 2H); 1.95 (bs, 2H); 2.52-2.54 (m, 3H); 2.76(bs, 4H); 3.08 (bs, 3H); 3.84 (s, 3H); 4.62 (s, 2H); 4.63 (s, 2H); 6.78(d, 1H, J=7.2 Hz); 6.93 (bs, 2H); 7.05 (d, 2H, J=9.2 Hz); 7.20 (t, 2H,J=7.6 and 7.2 Hz); 7.49-7.57 (m, 2H); 7.87-7.89 (m, 2H); 7.96-7.98 (m,2H); 12.45 (s, 1H); MS for C₃₂H₃₅N₃O₅ m/z 542.02 (M+H)⁺.

Preparation of tert-butyl3-((8-(4-(4-methoxyphenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (300mg, 0.71 mmol, 1 equiv), 4-iodo-1-(4-methoxyphenyl)butan-1-one (216.5mg, 0.71 mmol, 1 equiv), and potassium carbonate (285.2 mg, 2.136 mmol,3 equiv) in N,N-dimethylformamide was stirred at 68° C. for 16 h. Aftercooling the reaction mixture, the crude mixture was partitioned betweenethyl acetate and water. The organic layer was dried over MgSO₄,filtered, concentrated, and the crude residue was purified using theBiotage flash chromatography system (SNAP 10 g cartridge, R_(f)=0.4,gradient—1%-8% methanol in dichloromethane) to afford the title compoundas an oil (100 mg, 25%); MS for C₃₆H₄₃N₃O₅ m/z 598.3 (M+H)⁺.

Preparation of 4-chloro-1-(4-methoxyphenyl)butan-1-one

Sodium iodide was added to a solution of4-chloro-1-(4-methoxyphenyl)butan-1-one (1 g, 4.7 mmol, 1 equiv) inacetone, an the reaction mixture was refluxed for 16 h. Upon cooling,the reaction was concentrated in vacuo and the crude mixture waspartitioned between dichloromethane and water. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The residue waspurified using the Biotage flash chromatography system (SNAP 50 gcartridge, R_(f)=0.7, gradient—5%-25% ethyl acetate in hexanes) toafford the title compound as a brownish green solid (1.13 g, 79%); MSfor C₁₁H₁₃ClO₂ m/z 214.1 (M+H)⁺.

Example 58 Compound 92 tert-butyl3-((8-(3-(3,3-difluoro-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (300mg, 0.71 mmol, 1 equiv), 1-(3-chloropropyl)-3,3-difluoroindolin-2-one(206.5 mg, 0.71 mmol, 1 equiv), sodium iodide (42.7 mg, 0.285 mmol, 0.4equiv), and potassium carbonate (295.2 mg, 2.136 mmol, 3 equiv) in2-butanone was stirred at 81° C. for 16 h. After cooling the reactionmixture, the crude mixture was partitioned between ethyl acetate andwater. The organic layer was dried over MgSO₄, filtered, concentrated,and the crude residue was purified using preparatory thin layerchromatography in 5% methanol in dichloromethane to afford the titlecompound as cream crystals (210 mg, 46.8%); ¹H NMR (400 MHz, DMSO-d₆): δ1.52 (s, 9H); 1.60 (d, 2H, J=13.2 Hz); 1.84 (t, 2H, J=6.8 and 6.4 Hz);2.38 (t, 2H, J=6.4 Hz); 2.51 (bs, 2H); 2.71 (bs, 4H); 3.80 (t, 2H, J=6.8Hz); 4.58 (s, 2H); 4.60 (s, 2H); 6.78 (t, 1H, J=7.2 Hz); 6.83 (d, 2H,J=8.4 Hz); 7.21-7.25 (m, 3H); 7.36 (d, 1H, J=8 Hz); 7.48-7.59 (m, 3H);7.70 (d, 1H, J=6.8 Hz); 7.79 (s, 1H); 7.82-7.84 (m, 2H); MS forC₃₆H₄₀F₂N₄O₄ m/z 631.11 (M+H)⁺.

Preparation of 1-(3-chloropropyl)-3,3-difluoroindolin-2-one

A solution of 3,3-difluoroindolin-2-one (836.6 mg, 4.95 mmol, 1 equiv)in N,N-dimethylformamide was cooled to 0° C. Sodium hydride (60%dispersion) (217.6 mg, 5.44 mmol, 1.1 equiv) was slowly added and thereaction was stirred as such until all bubbling had stopped.1-bromo-3-chloropropane (1.46 ml, 14.85 mmol, 3 equiv) was added to thereaction mixture in one portion. The reaction was allowed to warm toambient temperature and stirred as such for 16 h. The crude mixture waspartitioned between ethyl acetate and water. The organic layer was driedover MgSO₄, filtered, concentrated, and the residue was purified usingthe Biotage flash chromatography system (SNAP 50 g cartridge, R_(f)=0.5,gradient—5%-30% ethyl acetate in hexanes) to afford the title compoundas a yellow oil (1.22 g, quant); MS for C₁₁H₁₀ClF₂NO m/z 247.01 (M+H)⁺.

Example 59 Compound 93 tert-butyl3-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (300mg, 0.71 mmol, 1 equiv), 1-(3-chloropropyl)-3,3-dimethylindolin-2-one(200.8 mg, 0.71 mmol, 1 equiv), sodium iodide (42.7 mg, 0.285 mmol, 0.4equiv), and potassium carbonate (295.2 mg, 2.136 mmol, 3 equiv) in2-butanone was stirred at 81° C. for 16 h. After cooling the reactionmixture, the crude mixture was partitioned between ethyl acetate andwater. The organic layer was dried over MgSO₄, filtered, concentrated,and the crude residue was purified using preparatory thin layerchromatography in 5% methanol in dichloromethane to afford the titlecompound as cream crystals (210 mg, 47.4%); ¹H NMR (400 MHz, DMSO-d₆): δ1.27 (s, 6H); 1.52 (s, 9H); 1.63 (d, 2H, J=12.4 Hz); 1.79 (bs, 2H); 2.36(bs, 2H); 2.52-2.59 (m, 2H); 2.66-2.73 (m, 4H); 3.75 (t, 2H, J=6.8 Hz);4.59 (s, 2H); 4.61 (s, 2H); 6.77 (t, 1H, J=6.8 and 7.2 Hz); 6.85 (d, 2H,J=8.4 Hz); 7.03 (t, 1H, J=7.6 and 6.8 Hz); 7.13 (d, 1H, J=7.6 Hz); 7.23(t, 3H, J=8 and 7.6 Hz); 7.35 (d, 1H, J=7.2 Hz); 7.48-7.55 (m, 2H); 7.79(s, 1H); 7.82-7.84 (m, 1H); MS for C₃₈H₄₆N₄O₄ m/z 623.18 (M+H)⁺.

Preparation of 1-(3-chloropropyl)-3,3-dimethylindolin-2-one

A solution of 3,3-dimethylindolin-2-one (1.843 g, 11.43 mmol, 1 equiv)in N,N-dimethylformamide was cooled to 0° C. Sodium hydride (60%dispersion) (503 mg, 12.58 mmol, 1.1 equiv) was slowly added and thereaction was stirred as such until all bubbling had stopped.1-bromo-3-chloropropane (3.37 ml, 34.3 mmol, 3 equiv) was added to thereaction mixture in one portion. The reaction was allowed to warm toambient temperature and stirred as such for 16 h. The crude mixture waspartitioned between ethyl acetate and water. The organic layer was driedover MgSO₄, filtered, concentrated, and the residue was purified usingthe Biotage flash chromatography system (SNAP 50 g cartridge, R_(f)=0.5,gradient—5%-30% ethyl acetate in hexanes) to afford the title compoundas a light orange oil (2.38 g, 87%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.26(s, 6H); 1.98-2.14 (m, 2H); 3.65 (t, 2H, J=6 and 6.8 Hz); 3.77-3.81 (m,2H); 7.02-7.07 (m, 2H); 7.24-7.28 (m, 1H); 7.33-7.35 (m, 1H); MS forC₁₃H₁₆ClNO m/z 237.99 (M+H)⁺.

Example 60 Compound 943-((8-(3-(3,3-difluoro-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of tert-butyl3-((8-(3-(3,3-difluoro-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(210 mg, 0.333 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 4 h. The mixture wasconcentrated in vacuo and the crude residue was purified usingpreparatory high performance liquid chromatography to afford the acetatesalt of the title compound as a white solid (80 mg, 42%); ¹H NMR (400MHz, DMSO-d₆): δ 1.64 (d, 2H, J=12.8 Hz); 1.87 (d, 2H, J=6 Hz); 2.40 (t,2H, J=6.4 Hz); 2.51 (bs, 2H); 2.81 (bs, 4H); 3.80 (t, 2H, J=6.8 Hz);4.59 (s, 2H); 4.61 (s, 2H); 6.78 (t, 1H, J=7.2 and 7.6 Hz); 6.85 (d, 2H,J=8 Hz); 7.20-7.24 (m, 3H); 7.36 (d, 1H, J=8 Hz); 7.48-7.53 (m, 2H);7.59 (t, 1H, J=8 and 7.6 Hz); 7.71 (d, 1H, J=7.6 Hz); 7.87 (d, 1H, J=2Hz); 7.88 (d, 2H, J=2 Hz); 12.45 (bs, 1H); MS for C₃₂H₃₂F₂N₄O₄ m/z575.03 (M+H)⁺.

Example 61 Compound 1003-((8-(3-(6-Chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of tert-butyl3-((8-(3-(6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(100 mg, 0.16 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxanewas stirred at ambient temperature for 4 h. The mixture was concentratedin vacuo and the crude residue was purified using preparatory highperformance liquid chromatography to afford the acetate salt of thetitle compound as a white solid (22 mg, 24%); ¹H NMR (400 MHz, DMSO-d₆):1.61 (d, 2H, J=13.2 Hz); 1.83 (t, 2H, J=6.8 Hz); 2.37 (t, 2H, J=7.2 and6.8 Hz); 2.54-2.58 (m, 2H); 2.67-2.72 (m, 4H); 3.85 (t, 2H, J=6.8 Hz);4.58 (s, 2H); 4.61 (s, 2H); 6.77 (t, 1H, J=7.6 and 7.2 Hz); 6.85 (d, 2H,J=7.2 Hz); 6.98-7.01 (m, 2H); 7.20-7.24 (m, 3H); 7.47-7.53 (m, 2H);7.86-7.88 (m, 2H); 11.01 (bs, 1H); MS for C₃₁H₃₂ClN₅O₄ m/z 574 (M+H)⁺.

Preparation of tert-butyl3-((8-(3-(6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (329mg, 0.7807 mmol, 1 equiv),6-chloro-1-(3-chloropropyl)-1H-benzo[d]imidazol-2(3H)-one (219 mg,0.7807 mmol, 1 equiv), sodium iodide (46.81 mg, 0.312 mmol, 0.4 equiv),and potassium carbonate (323.7 mg, 2.34 mmol, 3 equiv) in 2-butanone wasstirred at 81° C. for 16 h. After cooling the reaction mixture, thecrude mixture was partitioned between ethyl acetate and water. Theorganic layer was dried over MgSO₄, filtered, concentrated, and thecrude residue was purified using preparatory thin layer chromatographyin 10% methanol in dichloromethane to afford the title compound as awhite powder (100 mg, ˜20%); MS for C₃₅H₄₀ClN₅O₄ m/z 630.15 (M+H)⁺.

Preparation of 6-chloro-1-(3-chloropropyl)-1H-benzo[d]imidazol-2(3H)-one

Sodium hydride (60% dispersion) (521.8 mg, 13.04 mmol, 1.1 equiv) wasadded to a solution of 5-chloro-1H-benzo[d]imidazol-2(3H)-one (2 g,11.86 mmol, 1 equiv) in N,N-dimethylformamide (50 ml), stirred atambient temperature under an atmosphere of nitrogen. After 75 minutes asolution of di-tert-butyl dicarbonate (2.59 g, 11.86 mmol, 1 equiv) inN,N-dimethylformamide (10 ml) was added drop-wise and the mixturestirred for 16 h. The solvent was removed in vacuo and the residue wasdiluted with sat. ammonium chloride solution. The mixture was extractedwith ethyl acetate, the organic layer dried over MgSO₄, filtered andconcentrated in vacuo. The resulting residue was chromatographed usingthe Biotage flash chromatography system (SNAP 50 g cartridge, R_(f)=0.3,gradient—5%-30% ethyl acetate in hexanes) to afford the tert-butyl5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate as a creampowder (1.41 g, 45%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.57 (s, 9H); 7.01(d, 1H, J=2 Hz); 7.09 (dd, 1H, J=2 Hz); 7.61 (d, 1H, J=9.2 Hz); 11.40(s, 1H); MS for C₁₂H₁₃ClN₂O₃ m/z 268.94 (M+H)⁺.

Sodium hydride (60% dispersion) (169.4 mg, 4.24 mmol, 1.2 equiv) wasadded to a solution of tert-butyl6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (948 mg,3.53 mmol, 1 equiv) in N,N-dimethylformamide. 1-bromo-3-chloropropane(1.04 ml, 10.59 mmol, 3 equiv) was added and the mixture was stirred atambient temperature for 16 h. The mixture was partitioned between ethylacetate and water, the organic layer was dried over MgSO₄, filtered,concentrated in vacuo and the residue was chromatographed using theBiotage flash chromatography system (SNAP 50 g cartridge, R_(f)=0.45,5%-25% ethyl acetate in hexanes) to afford the tert-butyl5-chloro-3-(3-chloropropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylateas a syrup (528 mg, 43.5%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.59 (s, 9H);2.09 (d, 2H, J=6.4 Hz, J=7.2 Hz); 3.68 (t, 2H, J=6.4 Hz, J=6.8 Hz); 3.92(t, 2H, J=7.2 Hz, J=6.8 Hz); 7.29 (m, 2H); 7.71 (d, 1H, J=1.2 Hz); MSfor C₁₅H₁₈Cl₂N₂O₃ m/z 346.1 (M+H)⁺.

A solution of tert-butyl5-chloro-3-(3-chloropropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate(528 mg, 1.53 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxanewas stirred at ambient temperature for 2 hours. The reaction mixture wasconcentrated and dried in vacuo to afford the hydrogen chloride salt ofthe title compound as a cream powder (507 mg, quant); ¹H NMR (400 MHz,DMSO-d₆): δ 2.03-2.12 (m, 2H); 3.63-3.72 (m, 2H); 3.90 (t, 2H, J=7.2 and6.8 Hz); 7.00 (d, 1H, J=2 Hz); 7.02 (dd, 1H, J=2 Hz); 7.15 (d, 1H, J=8Hz); MS for C₁₀H₁₀Cl₂N₂O m/z 244.93 (M+H)⁺.

Example 62 Compound 1022-Methyl-2-(4-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenoxy)propanoicacid

To tert-butyl2-methyl-2-(4-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenoxy)propanoate(0.2 g, 0.3 mmol) was added 4M solution of HCl in dioxane (3 mL). Afterstirring at room temperature for 4 hours, the reaction mixture wasconcentrated in vacuo and lyophilized in acetonitrile/water (1:1) toobtain the title compound as a hydrochloride salt (0.19 g, 99%); ¹H NMR(DMSO-d₆): δ 1.49 (s, 6H), 1.90 (d, 2H, J=14.4 Hz), 2.12-2.15 (m, 2H),2.87-2.93 (m, 2H), 3.19-3.22 (m, 2H), 3.44-3.72 (m, 4H), 3.90 (t, 2H,J=6.4 Hz), 4.48 (s, 2H), 4.60 (s, 2H), 6.77-6.81 (m, 3H), 6.97-7.05 (m,5H), 7.19-7.23 (m, 5H), 10.39 (br, 1H), 10.90 (s, 1H), 13.01 (br, 1H);MS for C₃₄H₃₉N₅O₅ m/z 598.21 (M+H)⁺.

Preparation of tert-butyl2-methyl-2-(4-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenoxy)propanoate

To a solution of benzyl3-(4-(1-tert-butoxy-2-methyl-1-oxopropan-2-yloxy)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.69 g, 1.12 mmol) in 1:1 solution of ethyl acetate/methanol (20 mL),was added 10 wt % palladium on carbon (0.2 g). After stirring underhydrogen at room temperature and atmospheric pressure for 2 hours, thereaction mixture was filtered, washed with methanol, concentrated invacuo to obtain tert-butyl2-methyl-2-(4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenoxy)propanoate(0.5 g, 93%).

To a solution of tert-butyl2-methyl-2-(4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenoxy)propanoate(0.22 g, 0.46 mmol) and potassium carbonate (0.095 g, 0.69 mmol) inN,N-dimethylformamide (4 mL), was added1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.139 g, 0.46 mmol).After stirring at 55° C. for 16 hours, the reaction mixture was dilutedwith ethyl acetate (100 mL), washed with water and brine. The organicphase was dried over MgSO₄, filtered, concentrated and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain the titlecompound (0.26 g, 86%); ¹H NMR (DMSO-d₆): δ 1.35 (s, 9H), 1.49 (s, 6H),1.56 (d, 2H, J=13.6 Hz), 1.82 (t, 2H, J=6.4 Hz), 2.32-2.34 (m, 2H),2.45-2.50 (m, 2H), 2.66-2.72 (m, 4H), 3.85 (t, 2H, J=6.8 Hz), 4.45 (s,2H), 4.53 (s, 2H), 6.77-6.84 (m, 5H), 6.96 (d, 3H, J=3.2 Hz), 7.17-7.24(m, 5H), 10.79 (s, 1H); MS for C₃₈H₄₇N₅O₅ m/z 654.18 (M+H)⁺.

Preparation of benzyl3-(4-(1-tert-butoxy-2-methyl-1-oxopropan-2-yloxy)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a cooled (0° C.) solution of tert-butyl2-(4-(hydroxymethyl)phenoxy)-2-methylpropanoate (0.5 g, 2.58 mmol) andtriethylamine (0.72 mL, 5.16 mmol, d=0.726) in dichloromethane (10 mL),was added methanesulfonyl chloride (0.22 mL, 2.84 mmol, d=1.474). Afterstirring at 0° C. for an hour, the reaction mixture was washed withdilute citric acid, water and brine. The organic phase was dried overMgSO₄, filtered, concentrated in vacuo to obtain tert-butyl2-methyl-2-(4-((methylsulfonyloxy)methyl)phenoxy) propanoate.

To a solution of benzyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.5 g, 1.37mmol) and potassium carbonate (0.28 g, 2.06 mmol) inN,N-dimethylformamide (10 mL), was added tert-butyl2-methyl-2-(4-((methylsulfonyloxy)methyl)phenoxy)propanoate (0.48 g,1.37 mmol). After stirring at 55° C. for 18 hours, the reaction mixturewas diluted with ethyl acetate (50 mL), washed with dilute citric acid,water and brine. The organic phase was dried over MgSO₄, filtered, andisolated by Biotage flash chromatography (10-75% ethyl acetate/hexanes)to obtain the title compound (0.7 g, 83%); ¹H NMR (DMSO-d₆): δ 1.35 (s,9H), 1.48 (s, 6H), 1.67 (d, 2H, J=13.6 Hz), 2.32-2.38 (m, 2H), 3.56 (br,2H), 3.98-4.01 (m, 2H), 4.48 (s, 2H), 4.56 (s, 2H), 5.15 (br, 2H), 6.67(d, 2H, J=8 Hz), 6.75-6.80 (m, 3H), 7.15-7.22 (m, 4H), 7.32-7.38 (m,5H); MS for C₃₆H₄₃N₃O₆ m/z 614.15 (M+H)⁺.

Example 63 Compound 108 tert-Butyl3-((8-(3-(1H-indazol-3-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

Totert-3-((8-(3-(1H-indazol-3-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.047 g, 0.08 mmol) was added 4M solution of HCl in dioxane (1 mL).After stirring at room temperature for 3 hours, the reaction mixture wasconcentrated in vacuo and lyophilized in acetonitrile/water (1:1) toobtain the title compound as a hydrochloride salt (0.045 g, 99%); ¹H NMR(DMSO-d₆): δ 1.90 (d, 2H, J=14 Hz), 2.26 (br, 2H), 3.01 (t, 2H, J=7.6Hz), 3.24 (br, 2H), 3.45-3.70 (m, 6H), 4.64 (d, 4H, J=4 Hz), 6.79 (t,1H, J=6.8 Hz), 7.03-7.11 (m, 3H), 7.20 (t, 2H, J=7.2 Hz), 7.33 (t, 1H,J=7.6 Hz), 7.47-7.58 (m, 3H), 7.79 (d, 1H, J=8 Hz), 7.88 (d, 2H, J=9.2Hz), 10.73 (br, 1H), 12.77 (br, 1H); MS for C₃₁H₃₃N₅O₃ m/z 524.07(M+H)⁺.

Preparation of tert-butyl3-((8-(3-(1H-indazol-3-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2g, 0.47 mmol), potassium carbonate (0.097 g, 0.7 mmol) and sodium iodide(0.021 g, 0.14 mmol) in 2-butanone (5 mL), was added3-(3-chloropropyl)-1H-indazole (0.092 g, 0.47 mmol). After stirring at78° C. for 18 hours, the reaction mixture was filtered, concentrated andisolated by preparatory TLC (10% methanol/dichloromethane) to obtain thetitle compound (0.06 g, 22%); ¹H NMR (DMSO-d₆): δ 1.52 (s, 9H), 1.64 (d,2H, J=14 Hz), 1.95 (t, 2H, J=6.4 Hz), 2.59-2.85 (m, 8H), 2.96 (t, 2H,J=7.6 Hz), 4.60 (d, 4H, J=9.6 Hz), 6.76 (t, 1H, J=7.2 Hz), 6.85 (d, 2H,J=8 Hz), 7.06 (t, 1H, J=6.8 Hz), 7.21 (t, 2H, J=7.6 Hz), 7.31 (t, 1H,J=7.2 Hz), 7.44-7.53 (m, 3H), 7.74-7.84 (m, 3H), 12.63 (s, 1H); MS forC₃₅H₄₁N₅O₃ m/z 580.13 (M+H)⁺.

Example 64 Compound 1103-((8-(3-(2-(tert-Butoxycarbonyl)-1H-indol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To a solution of tert-butyl1-(3-(3-(3-(benzyloxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-2-carboxylate(0.27 g, 0.32 mmol) in MeOH (5 mL), was added 10%/wt palladium on carbon(0.080 g). The reaction mixture was hydrogenated at 50 psi for 48 hours.It was filtered over Celite, and isolated by preparatory thin layerchromatography in 10% methanol in dichloromethane to obtain the titlecompound (0.060 g, 30%); ¹H NMR (DMSO-d₆): δ 1.56 (s, 9H), 1.66 (d, 2H,J=14 Hz), 1.95 (t, 2H, J=6.4 Hz), 2.50-2.66 (m, 4H), 2.88 (bs, 4H),4.59-4.64 (m, 6H), 6.78 (t, 1H, J=7.2 Hz), 6.88 (d, 2H, J=8.4 Hz), 7.10(t, 1H, J=7.2 Hz), 7.19-7.31 (m, 3H), 7.48-7.54 (m, 2H), 7.67 (t, 2H,J=8.4 Hz), 7.87 (d, 2H, J=6.4 Hz), 8.13 (s, 1H), 12.75 (bs, 1H); MS forC₃₇H₄₂N₄O₅ m/z 623.16 (M+H)⁺.

Preparation of tert-butyl1-(3-(3-(3-(benzyloxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-2-carboxylate

A mixture of benzyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (807mg, 1.65 mmol, 1 equiv), tert-butyl1-(3-chloropropyl)-1H-indole-2-carboxylate (507 mg, 1.65 mmol, 1 equiv),sodium iodide (123.3 mg, 0.823 mmol, 0.5 equiv) and potassium carbonate(684.1 mg, 4.95 mmol, 3 equiv) in 2-butanone was stirred at 81° C. for16 h. After cooling the reaction mixture, the crude mixture waspartitioned between ethyl acetate and water. The organic layer was driedover MgSO₄, filtered, concentrated, and the crude residue was purifiedusing the Biotage flash chromatography system (SNAP 50 g cartridge,R_(f)=0.2, gradient—10%-50% ethyl acetate in hexanes) to afford thetitle compound as an oil (230 mg, 19%); MS for C₄₄H₄₈N₄O₅ m/z 713.37(M+H)⁺.

Preparation of benzyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(637 mg, 1.923 mmol, 1 equiv), benzyl 3-(chloromethyl)benzoate (500 mg,1.923 mmol, 1 equiv) and potassium carbonate (797.3 mg, 5.769 mmol, 3equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. Thereaction was partitioned between ethyl acetate and water. The organiclayer was further washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The resulting residue was purified using theBiotage flash chromatography system (SNAP, 50 g cartridge, R_(f)=0.4,gradient—5%-30% ethyl acetate in hexanes) to afford the tert-butyl3-(3-(benzyloxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylateas an oil (913 mg, 85.6%). MS for C₃₃H₃₇N₃O₅ m/z 556.27 (M+H)⁺.

A solution of tert-butyl3-(3-(benzyloxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(913 mg, 1.646 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 4-5 h. The mixture wasconcentrated in vacuo and the residue was lyophilized to afford thehydrogen chloride salt of the title compound as a cream solid (747 mg,quant); MS for C₂₈H₂₉N₃O₃ m/z 456.04 (M+H)⁺.

Preparation of tert-butyl 1-(3-chloropropyl)-1H-indole-2-carboxylate

Indole-2-carboxylic acid (1 g, 3.71 mmol, 1 equiv) was suspended intoluene and the mixture was heated to refluxing temperatures.N,N-dimethylformamide di-tert-butyl acetal (5.476 ml, 22.84 mmol, 4equiv) was added dropwise to the refluxing mixture within 30 minutes.Refluxing was continued for an additional 30-45 minutes after which itwas cooled and stirred at ambient temperature for 16 h. The reaction wasdiluted with ether and the organic layer was washed with sodiumbicarbonate (sat), water and brine. The ether layer was dried overMgSO₄, filtered, concentrated in vacuo and purified using the Biotageflash chromatography system (SNAP 50 g cartridge, R_(f)=0.4,gradient—1%-10% ethyl acetate in hexanes) to afford the tert-butyl1H-indole-2-carboxylate as a white powder (1.15 g, 86.8%); MS forC₁₃H₁₅NO₂ m/z 217.99 (M+H)⁺.

To a cold solution of tert-butyl 1H-indole-2-carboxylate (1.15 g, 4.94mmol, 1 equiv) in dimthylformamide sodium hydride (60% dispersion) (237mg, 5.92 mmol, 1.2 equiv) was added and the reaction stirred until allthe sodium hydride has been consumed. 1-bromo-3-chloropropane (1.46 ml,14.88 mmol, 3 equiv) was added and the reaction stirred at 60° C. for 16h. The reaction was partitioned between ethyl acetate and water. Theorganic layer was further washed with brine, dried over MgSO₄, filteredand concentrated in vacuo. The resulting residue was purified using theBiotage flash chromatography system (SNAP, 50 g cartridge, R_(f)=0.5,gradient—5%-25% ethyl acetate in hexanes) to afford the title compoundas an oil (1.52 g, quant); MS for C₁₆H₂₀ClNO₂ m/z 293.12 (M+H)⁺.

Example 65 Compound 1203-((8-(3-(3-Cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl3-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.27 g, 0.42 mmol) was added 4M solution of HCl in dioxane (4 mL) andtriethylsilane (0.1 mL). After stirring at room temperature for 3 hours,the reaction mixture was concentrated in vacuo and lyophilized inacetonitrile/water (1:1) to obtain the title compound as a hydrochloridesalt (0.215 g, 83%); ¹H NMR (DMSO-d₆): δ 0.88-0.90 (m, 2H), 1.01-1.06(m, 2H), 1.90 (d, 2H, J=14.4 Hz), 2.12 (br, 2H), 2.87-2.91 (m, 3H), 3.21(br, 2H), 3.45-3.69 (m, 4H), 3.90 (t, 2H, J=7.2 Hz), 4.64 (d, 4H, J=4.4Hz), 6.80 (t, 1H, J=7.2 Hz), 7.00 (d, 2H, J=8.4 Hz), 7.07-7.09 (m, 2H),7.19-7.28 (m, 4H), 7.48-7.57 (m, 2H), 7.88 (d, 2H, J=7.2 Hz), 10.33 (br,1H), 13.02 (br, 1H); MS for C₃₄H₃₇N₅O₄ m/z 580.13 (M+H)⁺.

Preparation of tert-butyl3-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2g, 0.47 mmol), potassium carbonate (0.097 g, 0.7 mmol) and sodium iodide(0.021 g, 0.14 mmol) in 2-butanone (5 mL), was added1-(3-chloropropyl)-3-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (0.119 g,0.47 mmol). After stirring at 78° C. for 18 hours, the reaction mixturewas filtered, concentrated and isolated by preparatory TLC (10%methanol/dichloromethane) to obtain the title compound (0.27 g, 90%); ¹HNMR (DMSO-d₆): δ 0.84-0.88 (m, 2H), 1.01 (d, 2H, J=5.6 Hz), 1.51 (s,9H), 1.61 (d, 2H, J=14.4 Hz), 1.81 (br, 2H), 2.34 (t, 2H, J=6.8 Hz),2.48-2.55 (m, 2H), 2.67-2.71 (m, 4H), 2.85-2.88 (m, 1H), 3.86 (t, 2H,J=6.4 Hz), 4.59 (d, 4H, J=10 Hz), 6.77 (t, 1H, J=7.2 Hz), 6.85 (d, 2H,J=8 Hz), 7.03-7.05 (m, 2H), 7.18-7.24 (m, 4H), 7.48-7.54 (m, 2H), 7.79(s, 1H), 7.83 (d, 1H, J=7.2 Hz); MS for C₃₈H₄₅N₅O₄ m/z 636.26 (M+H)⁺.

Preparation of1-(3-chloropropyl)-3-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one

To a solution of 1-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (J. Med.Chem. 1997, 40(4), 586-593) (1.0 g, 5.75 mmol) and potassium carbonate(2.4 g, 17.2 mmol) in N,N-dimethylformamide (20 mL), was added1-bromo-3-chloropropane (1.7 mL, 17.2 mmol, d=1.6). After stirring at60° C. for 18 hours, the reaction mixture was diluted with ethyl acetate(100 mL), washed with dilute citric acid, water and brine. The organicphase was dried over MgSO₄, filtered and isolated by Biotage flashchromatography (10-100% ethyl acetate/hexanes) to obtain the titlecompound (0.93 g, 65%); ¹H NMR (DMSO-d₆): δ 0.84-0.88 (m, 2H), 0.99-1.03(m, 2H), 2.03-2.10 (m, 2H), 2.85-2.90 (m, 1H), 3.65 (t, 2H, J=6.4 Hz),3.88-3.92 (m, 2H), 7.04-7.09 (m, 2H), 7.14-7.22 (m, 2H); MS forC₁₃H₁₅ClN₂O m/z 251.02 (M+H)⁺.

Example 66 Compound 1233-((8-(3-(3,3-Dimethyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl3-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.16 g, 0.25 mmol) was added 4M solution of HCl in dioxane (2.5 mL) andtriethylsilane (0.05 mL). After stirring at room temperature for 4hours, the reaction mixture was concentrated in vacuo and lyophilized inacetonitrile/water (1:1) to obtain the title compound as a hydrochloridesalt (0.14 g, 90%); ¹H NMR (DMSO-d₆): δ 1.28 (s, 6H), 1.91 (d, 2H, J=14Hz), 2.07 (br, 2H), 2.71 (t, 2H, J=10 Hz), 3.17 (br, 2H), 3.45-3.71 (m,4H), 3.76 (t, 2H, J=7.2 Hz), 4.62 (s, 4H), 7.04-7.07 (m, 5H), 7.15 (d,1H, J=7.6 Hz), 7.27 (t, 1H, J=8 Hz), 7.36 (d, 1H, J=7.6 Hz), 7.50 (t,1H, J=8 Hz), 7.55 (d, 1H, J=7.6 Hz), 7.87 (dd, 2H, J=6.8 and 1.6 Hz),10.39 (br, 1H), 13.03 (br, 1H); MS for C₃₄H₃₇FN₄O₄ m/z 585.23 (M+H)⁺.

Preparation of tert-butyl3-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methylbenzoate

To a solution of benzyl3-(3-(tert-butoxycarbonyl)benzyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.82 g, 1.43 mmol) in methanol (10 mL), was added 10 wt % palladium oncarbon (0.2 g). After stirring under hydrogen at room temperature andatmospheric pressure for 4 hours, the reaction mixture was filtered,washed with methanol, concentrated in vacuo to obtain tert-butyl3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.62 g, 99%).

To a solution of tert-butyl3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(1.2 g, 2.84 mmol), sodium iodide (0.015 g, 0.1 mmol) and potassiumcarbonate (0.07 g, 0.51 mmol) in 2-butanone (3 mL), was added1-(3-chloropropyl)-3,3-dimethylindolin-2-one (0.081 g, 0.34 mmol). Afterstirring at 78° C. for 18 hours, the reaction mixture was filtered andisolated by preparatory TLC (10% methanol/dichloromethane) to obtain thetitle compound (0.17 g, 78%); ¹H NMR (DMSO-d₆): δ 1.26 (s, 6H), 1.51 (s,9H), 1.63 (d, 2H, J=12.4 Hz), 1.75-1.76 (m, 2H), 2.29-2.32 (m, 4H),2.66-2.67 (m, 4H), 3.72 (t, 2H, J=6.8 Hz), 4.57 (d, 2H, J=14.8 Hz), 6.91(s, 2H), 7.02 (t, 1H, J=7.2 Hz), 7.07-7.09 (m, 3H), 7.22 (t, 1H, J=7.2Hz), 7.34 (d, 1H, J=7.2 Hz), 7.47-7.54 (m, 2H), 7.78 (s, 1H), 7.82 (d,1H, J=6.8 Hz).

Preparation of benzyl3-(3-(tert-butoxycarbonyl)benzyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (2g, 8.02 mmol) in dichloromethane (30 mL) and pyridine (1.3 mL, 16.04mmol, d=0.978), was added benzyl chloroformate (1.17 mL, 8.18 mmol,d=1.195). After stirring at room temperature for 24 hours, the reactionmixture was diluted with dichloromethane (100 mL), washed with dilutecitric acid, water and brine. The organic phase was dried over MgSO₄,filtered and concentrated to obtain benzyl1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate(2.12 g).

To a solution of benzyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1 g, 2.61mmol) and potassium carbonate (0.54 g, 3.91 mmol) inN,N-dimethylformamide (20 mL), was addedtert-butyl-3-(bromomethyl)benzoate (0.74 g, 2.74 mmol). After stirringat 55° C. for 60 hours, the reaction mixture was diluted with ethylacetate (100 mL), washed with dilute citric acid, water and brine. Theorganic phase was dried over MgSO₄, filtered, and isolated by Biotageflash chromatography (10-75% ethyl acetate/hexanes) to obtain the titlecompound (0.82 g, 55%); ¹H NMR (DMSO-d₆): δ 1.54 (s, 9H), 1.74 (d, 2H,J=14 Hz), 2.08-2.13 (m, 2H), 3.56 (br, 2H), 3.95 (d, 2H, J=8.8 Hz), 4.60(d, 2H, J=13.2 Hz), 5.10 (s, 2H), 6.80-6.83 (m, 2H), 7.05 (t, 2H, J=8.8Hz), 7.32-7.37 (m, 5H), 7.48-7.55 (m, 2H), 7.80 (s, 1H), 7.83 (d, 1H,J=7.6 Hz); MS for C₃₃H₃₆FN₃O₅ m/z 574.11 (M+H)⁺.

Example 67 Compound 1263-((8-(3-(3-(3-methoxy-3-oxopropyl)-1H-indol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of tert-butyl3-((8-(3-(3-(3-methoxy-3-oxopropyl)-1H-indol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(400 mg, 0.637 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 3 h. The mixture wasconcentrated in vacuo and the crude residue was purified usingpreparatory high performance liquid chromatography to afford the acetatesalt of the title compound as a white solid (130 mg, 35.7%); ¹H NMR (400MHz, DMSO-d₆): δ 1.62 (d, 2H, J=13.2 Hz); 1.89-1.93 (m, 2H); 2.27 (t,2H, J=6.8 Hz); 2.59-2.72 (m, 8H); 2.95 (t, 2H, J=7.6 and 8 Hz); 3.57 (s,3H); 4.19 (t, 2H, J=6.8 and 6.4 Hz); 4.59 (s, 2H); 4.61 (s, 2H); 6.76(t, 1H, J=7.2 Hz); 6.87 (d, 2H, J=8 Hz); 6.97-7.01 (m, 1H); 7.07-7.11(m, 1H); 7.17 (s, 1H); 7.20-7.24 (m, 2H); 7.46-7.54 (m, 4H); 7.86-7.88(m, 2H); 13.01 (bs, 1H); MS for C₃₆H₄₀N₄O₅ m/z 609 (M+H)⁺.

Preparation of tert-butyl3-((8-(3-(3-(3-methoxy-3-oxopropyl)-1H-indol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (500mg, 1.186 mmol, 1 equiv) and methyl3-(1-(3-chloropropyl)-1H-indol-3-yl)propanoate (384.4 mg, 1.186 mmol, 1equiv), sodium iodide (88.88 mg, 0.593 mmol, 0.5 equiv) and potassiumcarbonate (492 mg, 3.56 mmol, 3 equiv) in 2-butanone was stirred at 81°C. for 16 h. After cooling the reaction mixture, the crude mixture waspartitioned between ethyl acetate and water. The organic layer was driedover MgSO₄, filtered, concentrated, and the crude residue was purifiedusing preparative thin layer chromatography in 5% methanol indichloromethane to afford the title compound as a white solid (442 mg,56%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.52 (s, 9H); 1.63 (d, 2H, J=12 Hz);1.90-1.96 (m, 2H); 2.24 (bs, 2H); 2.61-2.70 (m, 8H); 2.96 (t, 2H, J=7.6Hz); 3.57 (s, 3H); 4.20 (t, 2H, J=6.4 and 6.8 Hz); 4.59 (s, 2H); 4.61(s, 2H); 6.77 (t, 1H, J=7.2 and 7.6 Hz); 6.87 (d, 2H, J=8.4 Hz); 6.99(t, 1H, J=7.6 Hz); 7.10 (t, 1H, J=7.6 and 6.8 Hz); 7.17 (s, 1H); 7.24(t, 2H, J=7.2 and 8.4 Hz); 7.46-7.53 (m, 4H); 7.79-7.84 (m, 2H); MS forC₄₀H₄₈N₄O₅ m/z 665 (M+H)⁺.

Preparation of methyl 3-(1-(3-chloropropyl)-1H-indol-3-yl)propanoate

Sodium hydride (60% dispersion) (236 mg, 5.91 mmol, 1.2 equiv) wasslowly added to a cold mixture of methyl 3-(1H-indol-3-yl)propanoate (2g, 4.92 mmol, 1 equiv) in N,N-dimethylformamide. After all the sodiumhydride has reacted, 1-bromo-3-chloropropane (1.94 ml, 19.68 mmol, 4equiv) was added and the reaction stirred at 55° C. for 16 h. Uponcooling the reaction was partitioned between water and ethyl acetate.The organic layer was further washed with 1N hydrogen chloride, brine,dried over MgSO₄, filtered and concentrated in vacuo. The crude residuewas purified using the Biotage flash chromatography system (SNAP 50 gcartridge, R_(f)=0.5, gradient—1%-10% ethyl acetate in hexanes) toafford the title compound as a yellow oil (1.154 g, 83%); ¹H NMR (400MHz, DMSO-d₆): δ 2.12-2.27 (m, 2H); 2.65-2.70 (m, 2H); 2.93-2.98 (m,2H); 3.38-3.54 (m, 2H); 3.58 (s, 3H); 4.08-4.12 (m, 2H); 4.21-4.25 (m,2H); 7.02 (t, 1H, J=7.6 Hz); 7.12-7.15 (m, 2H); 7.43 (dd, 1H, J=3.2 and2.8 Hz); 7.52-7.55 (m, 1H); MS for C₁₅H₁₈ClNO₂ m/z 280 (M+H)⁺.

Example 68 Compound 1303-((4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, hydrochloride salt

tert-Butyl3-((4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.27 g, 0.435 mmol) and formic acid (4 mL) were stirred at roomtemperature for 20 hours. The reaction was evaporated to dryness and theresidue purified by PTLC (10% methanol/dichloromethane) to give productas an oil; ¹H NMR (DMSO-d₆); δ1.52 (m, 2H); 1.59 (m, 2H); 1.68 (d,J=13.6 Hz, 2H); 1.87 (m, 2H); 2.57-2.62 (m, 4H); 2.91 (m, 4H); 3.82 (t,J=6.4 Hz, 2H); 4.60 (s, 2H); 4.62 (s, 2H); 6.76 (t, J=7.2 Hz, 1H); 6.86(d, J=8.4 Hz, 2H); 6.96-7.03 (m, 2H); 7.17-7.23 (m, 4H); 7.48-7.55 (m,2H); 7.87-7.89 (m, 2H); 8.15 (s, 1H). The formate salt was dissolved in4M hydrochloric acid in 1,4-dioxane (5 mL) and then evaporated undervacuum. The residue was dissolved in acetonitrile (5 mL) and water (5mL) and lyophilized to give product as a white solid (0.17 g, 65%); HPLCrt 10.65 min; ¹H NMR (DMSO-d₆); δ1.54 (m, 2H); 1.62 (m, 2H); 1.90 (d,J=14.4 hz, 2H); 2.11 (m, 2H); 2.92-2.98 (m, 2H); 3.22 (m, 2H); 3.46-3.70(m, 4H); 3.85 (t, J=7.2 hz, 2H); 4.64 (s, 2H); 4.65 (s, 2H); 6.79 (t,J=7.6 hz, 1H); 7.00-7.06 (m, 4H); 7.19-7.29 (m, 4H); 7.49-7.58 (m, 2H);7.87-7.89 (m, 2H); 10.6 (br s, 1H); 13.1 (br s, 1H); MS for C₃₄H₃₆N₄O₄m/z 565 (M+H)⁺.

Preparation of tert-butyl3-((4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

tert-Butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate)(0.25 g, 0.593 mmol),1′-(3-chloropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one) (0.14 g,0.593 mol), sodium iodide (0.027 g, 0.178 mmol), and potassium carbonate(0.12 g, 0.890 mmol) in 2-butanone (8 mL) were heated at 78° C. for 4hours. The reaction was diluted with 10% methanol/dichloromethane,filtered, and evaporated. The residue was purified by PTLC (5%methanol/dichloromethane) to give product as a white solid (0.27 g,72%); ¹H NMR (DMSO-d₆); δ1.51 (s, 9H); 1.53-1.63 (m, 6H); 1.80 (m, 2H);2.37 (m, 2H); 2.51-2.63 (m, 2H); 2.63-2.76 (m, 4H); 3.82 (t, J=6.8 Hz,2H); 4.58 (s, 2H); 4.61 (s, 2H); 6.76 (t, J=7.2 Hz, 1H); 6.85 (d, J=8.4Hz, 2H); 6.98-7.00 (m, 2H); 7.19-7.24 (m, 4H); 7.49-7.56 (m, 2H); 7.79(s, 1H); 7.82-7.84 9M, 1H); MS for C₃₈H₄₄N₄O₄ m/z 621 (M+H)⁺.

Example 69 Compound 1313-((4-Oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl3-((4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.1 g, 0.18 mmol) was added 4M solution of HCl in dioxane (2 mL) andtriethylsilane (0.1 mL). After stirring at room temperature for 4 hours,the reaction mixture was concentrated in vacuo and isolated by reversephase HPLC to obtain the title compound as an acetate salt (0.044 g,43%); ¹H NMR (DMSO-d₆): δ 1.58 (d, 2H, J=13.6 Hz), 1.84 (t, 2H, J=6.8Hz), 2.42-2.53 (m, 4H), 2.74-2.78 (m, 4H), 3.05 (t, 2H, J=7.2 Hz), 4.58(d, 4H, J=13.2 Hz), 6.70-6.75 (m, 3H), 7.12 (t, 2H, J=7.2 Hz), 7.48-7.54(m, 3H), 7.63 (t, 2H, J=7.6 Hz), 7.85 (d, 2H, J=2 Hz), 7.98 (dd, 2H, J=8and 1.6 Hz); MS for C₃₁H₃₃N₃O₄ m/z 512.07 (M+H)⁺.

Preparation of tert-butyl3-((4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2g, 0.47 mmol), potassium carbonate (0.097 g, 0.7 mmol) and sodium iodide(0.021 g, 0.14 mmol) in 2-butanone (5 mL), was added4-chlorobutyrophenone (0.076 mL, 0.47 mmol, d=1.138). After stirring at78° C. for 18 hours, the reaction mixture was filtered, concentrated andisolated by preparatory TLC (10% methanol/dichloromethane) to obtain thetitle compound (0.11 g, 41%); MS for C₃₅H₄₁N₃O₄ m/z 568.16 (M+H)⁺.

Example 70 Compound 1372-((8-(3-(3,3-Dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl2-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.17 g, 0.27 mmol) was added 4M solution of HCl in dioxane (3 mL) andtriethylsilane (0.1 mL). After stirring at room temperature for 4 hours,the reaction mixture was concentrated in vacuo, washed with acetonitrileand lyophilized in acetonitrile/water (1:1) to obtain the title compoundas a hydrochloride salt (0.8 g); ¹H NMR (DMSO-d₆): δ 1.28 (s, 6H), 1.98(d, 2H, J=10.4 Hz), 2.07 (t, 2H, J=6.4 Hz), 2.90-2.96 (m, 2H), 3.27 (br,2H), 3.54-3.61 (m, 4H), 3.77 (t, 2H, J=6.8 Hz), 4.66 (s, 2H), 4.92 (s,2H), 6.80 (t, 1H, J=7.2 Hz), 6.98 (d, 2H, J=8 Hz), 7.06 (t, 1H, J=7.6Hz), 7.16 (d, 1H, J=7.6 Hz), 7.20-7.32 (m, 4H), 7.37 (d, 1H, J=7.2 Hz),7.42 (t, 1H, J=8 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.92 (d, 1H, J=8 Hz),10.21 (br, 1H), 13.19 (br, 1H); MS for C₃₄H₃₈N₄O₄ m/z 567.22 (M+H)⁺.

Preparation of tert-butyl2-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of benzyl3-(2-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.59 g, 1.06 mmol) in methanol (20 mL), was added 10 wt % palladium oncarbon (0.1 g). After stirring under hydrogen at room temperature andatmospheric pressure for 2 hours, the reaction mixture was filtered,washed with methanol, concentrated in vacuo to obtain tert-butyl2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.4g, 90%).

To a solution of tert-butyl2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.175 g, 0.42 mmol), sodium iodide (0.019 g, 0.13 mmol) and potassiumcarbonate (0.087 g, 0.63 mmol) in 2-butanone (5 mL), was added1-(3-chloropropyl)-3,3-dimethylindolin-2-one (0.098 g, 0.42 mmol). Afterstirring at 78° C. for 18 hours, the reaction mixture was filtered andisolated by preparatory TLC (10% methanol/dichloromethane) to obtain thetitle compound (0.18 g, 69%); ¹H NMR (DMSO-d₆): δ 1.26 (s, 6H), 1.57 (s,9H), 1.67 (d, 2H, J=12.4 Hz), 1.75-1.76 (m, 2H), 2.32-2.33 (m, 2H),2.50-2.72 (m, 6H), 3.74 (t, 2H, J=6.4 Hz), 4.61 (s, 2H), 4.84 (s, 2H),6.76 (t, 1H, J=7.2 Hz), 6.84 (d, 2H, J=8 Hz), 7.02 (t, 1H, J=6.8 Hz),7.13 (d, 1H, J=7.6 Hz), 7.23-7.31 (m, 4H), 7.34 (d, 1H, J=6.8 Hz), 7.41(t, 1H, J=7.2 Hz), 7.57 (t, 1H, J=8.8 Hz), 7.82 (d, 1H, J=7.2 Hz); MSfor C₃₈H₄₆N₄O₄ m/z 623.28 (M+H)⁺.

Preparation of benzyl3-(2-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of benzyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1 g, 2.91mmol) and potassium carbonate (0.6 g, 4.37 mmol) inN,N-dimethylformamide (20 mL), was addedtert-butyl-2-(bromomethyl)benzoate (0.79 g, 2.91 mmol). After stirringat 55° C. for 18 hours, the reaction mixture was diluted with ethylacetate (100 mL), washed with dilute citric acid, water and brine. Theorganic phase was dried over MgSO₄, filtered, and isolated by Biotageflash chromatography (10-60% ethyl acetate/hexanes) to obtain the titlecompound (0.59 g, 36%); ¹H NMR (DMSO-d₆): δ 1.57 (s, 9H), 1.77 (d, 2H,J=13.6 Hz), 2.40-2.49 (m, 2H), 3.57 (br, 2H), 4.00-4.03 (m, 2H), 4.64(s, 2H), 4.87 (s, 2H), 5.15 (br, 2H), 6.68 (d, 2H, J=8 Hz), 6.78 (t, 1H,J=6.8 Hz), 7.18 (t, 2H, J=7.6 Hz), 7.27-7.43 (m, 7H), 7.58 (t, 1H, J=8.4Hz), 7.83 (dd, 1H, J=8 and 1.6 Hz); MS for C₃₃H₃₇N₃O₅ m/z 556.12 (M+H)⁺.

Preparation of 1-(3-chloropropyl)-3,3-dimethylindolin-2-one

To a cooled (0° C.) solution of 3,3-dimethylindolin-2-one (2.15 g, 13.2mmol) in N,N-dimethylformamide (15 mL), was added sodium hydride (0.332g, 13.85 mmol), followed by addition of 1-bromo-3-chloropropane (2.6 mL,26.4 mmol, d=1.6). After stirring at room temperature for 18 hours, thereaction mixture was diluted with ethyl acetate (100 mL), washed withdilute citric acid, water and brine. The organic phase was dried overMgSO₄, filtered and isolated by Biotage flash chromatography (10-75%ethyl acetate/hexanes) to obtain the title compound (2.6 g, 83%); MS forC₁₃H₁₆ClNO m/z 237.99 (M+H)⁺.

Example 71 Compound 1383-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl3-((1-(4-fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(2.84 g, 0.31 mmol, 1 equiv) was added concentrated formic acid. Afterstirring at room temperature for 16 hours, the reaction mixture wasconcentrated in vacuo and purified using the Biotage flashchromatography system (SNAP 50 g cartridge, R_(f)=0.5, gradient—1%-15%methanol in dichloromethane). The pure fractions were evaporated todryness under reduced pressure. The pure residue was converted to thehydrogen chloride salt using 4M hydrogen chloride solution in dioxane.The resulting residue was lyophilized in acetonitrile/water (1:1) toobtain the title compound as a hydrogen chloride salt (1.8 g, 70%); ¹HNMR (DMSO-d₆): δ 1.50 (t, 2H, J=7.6 Hz), 1.57 (t, 2H, J=7.6 Hz), 1.70(d, 2H, J=14 Hz), 1.83 (t, 2H, J=6.8 Hz), 2.29-2.37 (m, 2H), 2.54 (t,2H, J=6.4 Hz), 2.87-2.89 (m, 4H), 3.80 (t, 2H, J=6.8 Hz), 4.57 (d, 4H,J=12 Hz), 6.91-7.23 (m, 8H), 7.48-7.51 (m, 2H), 7.86-7.88 (m, 2H), 8.14(s, 1H); MS for C₃₄H₃₅FN₄O₄ m/z 583.16 (M+H)⁺.

Preparation of tert-butyl3-((1-(4-fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methylbenzoate

To a solution of tert-butyl3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(3 g, 6.81 mmol, 1 equiv), sodium iodide (0.408 g, 2.72 mmol, 0.4 equiv)and potassium carbonate (2.35 g, 13.62 mmol, 2 equiv) in 2-butanone (5mL), was added1′-(3-chloropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one (1.61 g, 6.81mmol, 1 equiv). After stirring at 78° C. for 16 hours, the reactionmixture was filtered and isolated using the Biotage flash chromatographysystem (SNAP 100 g cartridge, Rf=0.5, gradient 50%-100% ethyl acetate inhexanes) to obtain the title compound (2.84 g, 63%); ¹H NMR (DMSO-d₆): δ1.52 (s, 9H), 1.57-1.65 (m, 6H), 1.77 (t, 2H, J=6.4 Hz), 2.25-2.37 (m,4H), 2.64-2.68 (m, 4H), 3.79 (t, 2H, J=6.8 Hz), 4.57 (d, 4H, J=13.2 Hz),6.91-7.20 (m, 8H), 7.48-7.51 (m, 2H), 7.78 (s, 1H), 7.83 (d, 1H, J=7.2Hz); MS for C₃₈H₄₃FN₄O₄ m/z 639.14 (M+H)⁺.

Preparation of1′-(3-chloropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one

To a cooled (0° C.) solution of spiro[cyclopropane-1,3′-indolin]-2′-one(prepared according to methods described in J. Med. Chem. 1987, 824-829;J. Med. Chem. 1992, 163-172; U.S. Pat. No. 5,182,397) (1.0 g, 6.21 mmol)in N,N-dimethylformamide (5 mL), was added sodium hydride (0.149 g, 6.21mmol), followed by addition of 1-bromo-3-chloropropane (0.733 mL, 7.45mmol, d=1.6). After stirring at room temperature for 18 hours, thereaction mixture was diluted with ethyl acetate (100 mL), washed withdilute citric acid, water and brine. The organic phase was dried overMgSO₄, filtered and isolated by Biotage flash chromatography (10-40%ethyl acetate/hexanes) to obtain the title compound (1.1 g, 68%); ¹H NMR(DMSO-d₆): δ 1.50-1.54 (m, 2H), 1.56-1.61 (m, 2H), 2.01-2.15 (m, 2H),3.67 (t, 2H, J=6.4 Hz), 3.86 (t, 2H, J=6.8 Hz), 6.97-7.03 (m, 2H), 7.11(d, 1H, J=8 Hz), 7.22-7.27 (m, 1H); MS for C₁₃H₁₄ClNO m/z 236.04 (M+H)⁺.

Example 72 Compound 1423-((4-oxo-1-phenyl-8-(4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, formate

tert-Butyl3-((4-oxo-1-phenyl-8-(4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.30 g, 0.542 mmol) and formic acid (8 mL) were stirred at roomtemperature for 20 hours. The reaction was evaporated to dryness and theresidue purified by PTLC (10% methanol/dichloromethane). The product wasdissolved in formic acid (5 mL) and then evaporated under vacuum. Theresidue was dissolved in acetonitrile (5 mL) and water (5 mL) andlyophilized to give product as a white solid (0.22 g, 80%); NMR(DMSO-d₆); δ1.54-1.63 (m, 4H); 1.67 (d, J=14 Hz, 2H); 2.57-2.69 (m, 6H);2.97 (m, 4H); 4.59 (s, 2H); 4.62 (s, 2H); 6.72 (t, J=7.2 Hz, 1H); 6.84(d, J=8.4 Hz, 2H); 7.12-7.21 (m, 5H), 7.25-7.28 (m, 2H); 7.47-7.51 (m,2H); 7.88-7.89 (m, 2H); 8.21 (s, 1H). HPLC rt 11.66 min; MS forC₃₁H₃₅N₃O₃ m/z 498 (M+H)⁺.

Preparation of tert-butyl3-((4-oxo-1-phenyl-8-(4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methylbenzoate

tert-Butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.25 g, 0.593 mmol), 1-iodo-4-butylbenzene (0.15 g, 0.593 mmol), andpotassium carbonate (0.12 g, 0.890 mmol) in N,N-dimethylformamide (8 mL)were stirred at 65° C. for 2 hours. The reaction was diluted with ethylacetate, washed with water and brine, dried (MgSO₄), and evaporated. Theresidue was purified by PTLC (5% methanol/dichloromethane) to giveproduct as an oil (0.30 g, 90%); MS for C₃₅H₄₃N₃O₃ m/z 554 (M+H)⁺.

Example 73 Compound 1433-((4-oxo-8-(4-oxo-4-(thiophen-2-yl)butyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, hydrochloride

tert-Butyl3-((4-oxo-8-(4-oxo-4-(thiophen-2-yl)butyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.29 g, 0.505 mmol) and formic acid (6 mL) were stirred at roomtemperature for 20 hours. The reaction was evaporated to dryness and theresidue purified by PTLC (10% methanol/dichloromethane) to give productas the formate salt; NMR (DMSO-d₆); δ1.63 (d, J=14 Hz, 2H); 1.87 (t,J=6.8 Hz, 2H); 2.52 (m, 4H); 2.88 (m, 4H); 3.01 (t, J=7.2 Hz, 2H); 4.58(s, 2H); 4.61 (s, 2H); 6.75 (t, J=7.6 Hz, 1H); 6.80 (d, J=8 Hz, 2H);7.17 (t, J=8.4 Hz, 2H); 7.24 (dd, J=3.6 Hz and 4.8 Hz, 1H); 7.48-7.54(m, 2H); 7.87-7.89 (m, 2H); 7.95-7.99 (m, 2H); 8.18 (s, 1H). The formatesalt was dissolved in 4M hydrochloric acid in dioxane (5 mL) and thenevaporated under vacuum. The residue was dissolved in acetonitrile (5mL) and water (5 mL) and lyophilized to give product as a white solid(0.22 g, 72%); HPLC rt 9.92 min; NMR (DMSO-d₆); δ1.90 (d, J=14.4 Hz,2H); 2.10 (m, 2H); 3.03 (m, 2H); 3.17 (t, J=7.2 Hz, 4H); 3.58-3.69 (m,4H); 4.65 (s, 2H); 4.66 (s, 2H); 6.80 (t, J=7.2 Hz, 1H); 7.07 (d, J=8.4Hz, 2H); 7.21 (dd, J=7.2 Hz and 8.4 Hz, 2H); 7.27 (dd, J=3.6 Hz and 4.8Hz, 1H); 7.52 (t, J=7.6 Hz, 1H); 7.57 (d, J=8 Hz, 1H); 7.88-7.90 (m,2H); 7.99 (dd, J=1.6 Hz and 4 Hz, 1H); 8.02 (dd, J=1.2 Hz and 4.8 Hz,1H); MS for C₂₉H₃₁N₃O₄S m/z 518 (M+H)⁺.

Preparation of tert-butyl3-((4-oxo-8-(4-oxo-4-(thiophen-2-yl)butyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methylbenzoate

tert-Butyl4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.25 g, 0.593 mmol), 4-iodo-1-(thiophen-2-yl)butan-1-one (0.17 g, 0.593mmol), and potassium carbonate (0.12 g, 0.890 mmol) inN,N-dimethylformamide (8 mL) were heated at 65° C. for 4 hours. Thereaction was diluted with ethyl acetate, washed with water and brine,dried (MgSO₄), and evaporated. The residue was purified by PTLC (5%methanol/dichloromethane) to give product as an oil (0.29 g, 84%); NMR(DMSO-d₆); δ1.52 (s, 9H); 1.57 (m, 2H); 1.85 (m, 2H); 2.33-2.49 (m, 4H);2.73 (m, 4H); 3.00 (m, 2H); 4.58 (s, 2H); 4.61 (m, 2H); 6.78 (m, 2H);7.18-7.26 (m, 4H); 7.48-7.55 (m, 2H); 7.80-7.84 (m, 2H); 7.96-8.00 (m,2H); MS for C₃₃H₃₉N₃O₄S m/z 574 (M+H)⁺.

Preparation of 4-iodo-1-(thiophen-2-yl)butan-1-one

4-Chloro-2-butyrothienone (2.00 g, 0.0106 mol) and sodium iodide (2.38g, 0.0159 mol) in acetone (30 mL) were refluxed overnight. The solventwas removed, the residue diluted with ether, washed with water andbrine, dried (MgSO₄) and evaporated. The residue was purified by Biotageflash column chromatography (5% ethyl acetate/hexanes) to give productas an oil (2.84 g, 96%); MS for C₈H₉IOS m/z 281 (M+H)⁺.

Example 74 Compound 1453-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To a solution of tert-butyl3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.2 g, 0.46 mmol), sodium iodide (0.021 g, 0.14 mmol) and potassiumbicarbonate (0.069 g, 0.69 mmol) in 2-butanone (5 mL), was added1-(3-chloropropyl)indolin-2-one (0.096 g, 0.46 mmol). After stirring at78° C. for 2 hours, the reaction mixture was filtered and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain tert-butyl3-((1-(4-fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.075 g, 27%).

To tert-butyl3-((1-(4-fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.07 g, 0.11 mmol) was added concentrated 4M HCl in dioxane (1.5 mL)and triethylsilane (0.05 mL). After stirring at room temperature for 18hours, the reaction mixture was concentrated in vacuo and isolated byreverse phase HPLC to obtain the title compound as an acetate salt(0.035 g, 52%); ¹H NMR (DMSO-d₆): δ 1.62 (d, 2H, J=13.6 Hz), 1.74 (t,2H, J=6.4 Hz), 2.24-2.28 (m, 2H), 2.36 (t, 2H, J=6.4 Hz), 2.68 (d, 4H,J=6.8 Hz), 3.52 (s, 2H), 3.70 (t, 2H, J=6.8 Hz), 4.56 (d, 4H, J=14 Hz),6.89-6.92 (m, 2H), 6.98 (t, 1H, J=7.2 Hz), 7.04-7.10 (m, 3H), 7.19-7.24(m, 2H), 7.48-7.51 (m, 2H), 7.86 (d, 2H, J=3.2 Hz); MS for C₃₂H₃₃FN₄O₄m/z 557.09 (M+H)⁺.

Preparation of 1-(3-chloropropyl)indolin-2-one

To a solution of oxindole (9.2 g, 69.1 mmol) and potassium carbonate(19.0 g, 138.2 mmol) in acetonitrile (100 mL), was added1-bromo-3-chloropropane (13.6 mL, 138.2 mmol, d=1.6). After stirring at80° C. for 18 hours, the reaction mixture was diluted with ethyl acetate(200 mL), washed with dilute citric acid, water and brine. The organicphase was dried over MgSO₄, filtered and isolated by Biotage flashchromatography (10-40% ethyl acetate/hexanes) to obtain the titlecompound (6.2 g, 43%); ¹H NMR (DMSO-d₆): δ 1.98-2.05 (m, 2H), 3.54 (s,2H), 3.67 (t, 2H, J=6.4 Hz), 3.77 (t, 2H, J=6.4 Hz), 6.98-7.03 (m, 2H),7.24-7.28 (m, 2H); MS for C₁₁H₁₂ClNO m/z 210.03 (M+H)⁺.

Example 75 Compound 1463-((8-(3-(3-methyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of tert-butyl3-((8-(3-(3-methyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(100 mg, 0.164 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 16 h. The mixture wasconcentrated and dried in vacuo to afford the hydrogen chloride salt ofthe title compound as a white powder (12 mg, 14%); ¹H NMR (400 MHz,DMSO-d₆): δ 1.34 (d, 3H, J=7.6 Hz); 1.63 (d, 2H, J=12.8 Hz); 1.79 (t,2H, J=6.8 Hz); 2.49 (bs, 2H); 2.56 (bs, 2H); 2.67-2.77 (m, 4H);3.45-3.51 (m, 1H); 3.7-3.75 (m, 2H); 4.59 (s, 2H); 4.61 (s, 2H); 6.77(t, 1H, J=7.2 and 7.6 Hz); 6.86 (d, 2H, J=8.4 Hz); 7.01 (t, 1H, J=7.2and 7.6 Hz); 7.10 (d, 1H, J=8 Hz); 7.19-7.25 (m, 3H); 7.31 (d, 1H, J=7.2Hz); 7.48-7.52 (m, 2H); 7.86-7.88 (m, 1H); 13.01 (bs, 1H); MS forC₃₃H₃₆N₄O₄ m/z 553.11 (M+H)⁺.

Preparation of tert-butyl3-((8-(3-(3-methyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (200mg, 0.475 mmol, 1 equiv), 1-(3-chloropropyl)-3-methylindolin-2-one (155mg, 0.665 mmol, 1.4 equiv), sodium iodide (28.5 mg, 0.19 mmol, 0.4equiv) and potassium carbonate (71.4 mg, 0.7125 mmol, 1.5 equiv) in2-butanone was stirred at 81° C. for 16 h. After cooling the reactionmixture, the crude mixture was partitioned between ethyl acetate andwater. The organic layer was dried over MgSO₄, filtered, concentrated,and the crude residue was purified using preparative thin layerchromatography in 7% methanol in dichloromethane to afford the titlecompound (100 mg, ˜30%); MS for C₃₇H₄₄N₄O₄ m/z 609.3 (M+H)⁺.

Preparation of 1-(3-chloropropyl)-3-methylindolin-2-one

To a mixture of 3-methylindolin-2-one (1 g, 6.79 mmol, 1 equiv) inacetonitrile, potassium carbonate (1.877 g, 13.58 mmol, 2.5 equiv)followed by 1-bromo-3-chloropropane (2.01 ml, 20.38 mmol, 3 equiv) wereadded. The reaction was refluxed for 16 h. Upon cooling water was addedand the mixture was extracted into ethyl acetate. The organic layer wasfurther washed with brine, dried over MgSO₄, filtered and concentratedin vacuo. The crude residue was purified using the Biotage flashchromatography system (SNAP 100 g cartridge, R_(f)=0.5, gradient—2%-20%ethyl acetate in hexanes) to afford the title compound as a yellow oil(230 mg, 15%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.31 (d, 3H, J=7.6 Hz);1.99-2.05 (m, 2H); 3.47-3.53 (m, 1H); 3.66 (t, 2H, J=6.4 Hz); 3.74-3.82(m, 2H); 7.04 (d, 2H; J=7.6 Hz); 7.24-7.27 (m, 1H); 7.3-7.32 (m, 1H); MSfor C₁₂H₁₄ClNO m/z 211.06 (M+H)⁺.

Example 76 Compound 1482-((4-Oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To a solution of tert-butyl2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (1.9g, 4.5 mmol), sodium iodide (0.27 g, 1.8 mmol) and potassium carbonate(1.24 g, 9.0 mmol) in 2-butanone (20 mL), was added1-(3-chloropropyl)indolin-2-one (0.945 g, 4.5 mmol). After stirring at78° C. for 4 hours, the reaction mixture was filtered and isolated byBiotage flash chromatography (50-100% ethyl acetate/hexanes) to obtaintert-butyl2-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.45 g, 17%).

To tert-butyl2-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.45 g, 0.76 mmol) was added concentrated 4M HCl in dioxane (10 mL).After stirring at room temperature for 18 hours, the reaction mixturewas concentrated in vacuo and washed with 1% methanol/dichloromethane toobtain the title compound as a hydrochloride salt (0.22 g, 50%); ¹H NMR(DMSO-d₆): δ 1.97-2.06 (m, 4H), 2.92 (t, 2H, J=10 Hz), 3.20 (br, 2H),3.53-3.57 (m, 6H), 3.76 (t, 2H, J=6.8 Hz), 4.66 (s, 2H), 4.92 (s, 2H),6.80 (t, 1H, J=7.6 Hz), 6.98-7.04 (m, 3H), 7.12 (d, 1H, J=7.6 Hz),7.20-7.32 (m, 5H), 7.42 (t, 1H, J=7.6 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.92(dd, 1H, J=7.6 and 1.2 Hz), 10.27 (br, 1H), 13.21 (s, 1H); MS forC₃₂H₃₄N₄O₄ m/z 539.15 (M+H)⁺.

Example 77 Compound 1492-((4-Cho-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl2-((4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.18 g, 0.29 mmol) was added concentrated formic acid (3 mL) andtriethylsilane (0.05 mL). After stirring at room temperature for 18hours, the reaction mixture was concentrated, taken in 4M HCl in dioxaneand lyophilized to obtain the title compound as a hydrochloride salt(0.165 g, 95%); ¹H NMR (DMSO-d₆): δ 1.52-1.63 (m, 4H), 1.98 (d, 2H,J=14.8 Hz), 2.08-2.10 (m, 2H), 2.92 (t, 2H, J=7.6 Hz), 3.21 (br, 2H),3.45-3.71 (m, 4H), 3.84 (t, 2H, J=6.8 Hz), 4.68 (s, 2H), 4.92 (s, 2H),6.80 (t, 1H, J=7.6 Hz), 6.98-7.05 (m, 4H), 7.20-7.32 (m, 5H), 7.42 (t,1H, J=7.6 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.92 (dd, 1H, J=8 and 1.6 Hz),10.32 (br, 1H), 13.19 (s, 1H); MS for C₃₄H₃₆N₄O₄ m/z 565.14 (M+H)⁺.

Preparation of tert-butyl2-((4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of tert-butyl2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2g, 0.47 mmol), sodium iodide (0.021 g, 0.14 mmol) and potassiumcarbonate (0.097 g, 0.7 mmol) in 2-butanone (5 mL), was added1′-(3-chloropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one (0.112 g,0.47 mmol). After stirring at 78° C. for 2 hours, the reaction mixturewas filtered and isolated by Biotage flash chromatography (1-10%methanol/dichloromethane) to obtain the title compound (0.18 g, 62%); ¹HNMR (DMSO-d₆): δ 1.51 (t, 4H, J=7.2 Hz), 1.57 (s, 9H), 1.67 (d, 2H,J=12.4 Hz), 1.79 (t, 2H, J=6.8 Hz), 2.36 (t, 2H, J=6.8 Hz), 2.54-2.74(m, 6H), 3.81 (t, 2H, J=7.2 Hz), 4.62 (s, 2H), 4.84 (s, 2H), 6.76 (t,1H, J=7.2 Hz), 6.84 (d, 2H, J=8 Hz), 6.96-7.02 (m, 2H), 7.17-7.27 (m,5H), 7.41 (t, 1H, J=6.8 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.83 (dd, 1H, J=8and 1.2 Hz); MS for C₃₈H₄₄N₄O₄ m/z 621.12 (M+H)⁺.

Example 78 Compound 1503-((1-cyclohexyl-8-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, hydrochloride

tert-butyl3-((1-cyclohexyl-8-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.39 g, 0.659 mmol) and 4M hydrochloric acid/1% triethylsilane in1,4-dioxane (6 mL) were stirred at room temperature for 4 hours. Thereaction was evaporated and the residue purified by PTLC (10%methanol/dichloromethane). The product obtained from PTLC wasredissolved in 4M hydrochloric acid in dioxane and evaporated. Theresidue was dissolved in acetonitrile (5 mL) and water (5 mL) andlyophilized to give product as a white solid (0.28 g, 75%); HPLC rt10.92 min; NMR (DMSO-d₆); δ1.02-1.08 (m, 1H); 1.18-1.28 (m, 4H);1.28-1.40 (m, 1H); 1.45-1.65 (m, 2H); 1.65-1.78 (m, 3H); 1.85-2.10 (m,3H); 2.33-2.50 (m, 2H); 3.10 (m, 2H); 3.22 (t, J=6.8 Hz, 2H); 3.49-3.56(m, 5H); 4.52 (s, 2H); 7.35-7.40 (m, 2H); 7.50 (m, 2H); 7.85-7.86 (m,2H); 8.05-8.09 (m, 2H); 10.6 (br s, 1H); 13.0 (br s, 1H); MS forC₃₁H₃₈FN₃O₄ m/z 536 (M+H)⁺.

Preparation of tert-butyl3-((1-cyclohexyl-8-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

tert-Butyl3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.353 g, 0.826 mmol), 4-iodo-4′-fluorobutyrophenone (0.27 g, 0.826mmol), and potassium carbonate (0.17 g, 1.24 mmol) inN,N-dimethylformamide (8 mL) were heated at 65° C. for 2 hours. Thereaction was diluted with ethyl acetate, washed with water and brine,dried (MgSO₄), and evaporated. The residue was purified by PTLC (5%methanol/dichloromethane) to give product as an oil (0.39 g, 80%); MSfor C₃₅H₄₆FN₃O₄ m/z 592 (M+H)⁺.

Example 79 Compound 1532-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl2-((1-(4-fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.062 g, 0.1 mmol) was added concentrated 4M HCl in dioxane (1.0 mL)and triethylsilane (0.05 mL). After stirring at room temperature for 3hours, the reaction mixture was concentrated in vacuo and lyophilized inacetonitrile:water (1:1) to obtain the title compound as a hydrochloridesalt (0.035 g, 52%); ¹H NMR (DMSO-d₆): δ 1.99-2.08 (m, 4H), 2.66 (t, 2H,J=12.4 Hz), 3.17-3.20 (m, 2H), 3.45-3.56 (m, 4H), 3.66-3.70 (m, 2H),3.75 (t, 2H, J=6.8 Hz), 4.64 (s, 2H), 4.91 (s, 2H), 7.00-7.12 (m, 6H),7.26-7.32 (m, 3H), 7.42 (t, 1H, J=7.2 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.91(dd, 1H, J=8 and 1.2 Hz), 10.05 (br, 1H), 13.18 (s, 1H); MS forC₃₂H₃₃FN₄O₄ m/z 557.06 (M+H)⁺.

tert-Butyl2-((1-(4-fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methylbenzoate

To a solution of benzyl3-(2-(tert-butoxycarbonyl)benzyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate(1.5 g, 2.61 mmol) in methanol (25 mL), was added 10 wt % palladium oncarbon (0.25 g). After stirring under hydrogen at room temperature andatmospheric pressure for 2 hours, the reaction mixture was filtered,washed with methanol, concentrated in vacuo to obtain tert-butyl2-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(1.1 g, 96%).

To a solution of tert-butyl2-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.175 g, 0.4 mmol), sodium iodide (0.018 g, 0.12 mmol) and potassiumcarbonate (0.083 g, 0.6 mmol) in 2-butanone (4 mL), was added1-(3-chloropropyl)indolin-2-one (0.095 g, 0.4 mmol). After stirring at78° C. for 18 hours, the reaction mixture was filtered and isolated byBiotage flash chromatography (1-10% methanol/dichloromethane) andpreparatory TLC (10% methanol/dichloromethane) to obtain the titlecompound (0.077 g, 31%); ¹H NMR (DMSO-d₆): δ 1.56 (s, 9H), 1.67 (d, 2H,J=12.4 Hz), 2.02 (br, 2H), 2.28-2.34 (m, 2H), 2.62-2.67 (m, 2H),3.17-3.23 (m, 2H), 3.52-3.56 (m, 4H), 3.72 (t, 2H, J=6.4 Hz), 4.61 (s,2H), 4.82 (s, 2H), 6.11-7.14 (m, 6H), 7.23-7.27 (m, 3H), 7.41 (t, 1H,J=7.6 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.82 (d, 1H, J=8 Hz); MS forC₃₆H₄₁FN₄O₄ m/z 613.15 (M+H)⁺.

Preparation of benzyl3-(2-(tert-butoxycarbonyl)benzyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of benzyl1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.6g, 4.17 mmol) and potassium carbonate (0.86 g, 6.3 mmol) inN,N-dimethylformamide (20 mL), was addedtert-butyl-2-(bromomethyl)benzoate (1.13 g, 4.17 mmol). After stirringat 60° C. for 24 hours, the reaction mixture was diluted with ethylacetate (200 mL), washed with dilute citric acid, water and brine. Theorganic phase was dried over MgSO₄, filtered, and isolated by Biotageflash chromatography (10-100% ethyl acetate/hexanes) to obtain the titlecompound (1.5 g, 63%); ¹H NMR (DMSO-d₆): δ 1.56 (s, 9H), 1.80 (d, 2H,J=14 Hz), 2.12 (t, 2H, J=10.8 Hz), 3.57 (br, 2H), 4.02 (d, 2H, J=6.8Hz), 4.61 (s, 2H), 4.85 (s, 2H), 5.10 (s, 2H), 6.79-6.82 (m, 2H), 7.06(t, 2H, J=9.2 Hz), 7.28-7.43 (m, 7H), 7.58 (t, 1H, J=7.6 Hz), 7.82 (dd,1H, J=8 and 1.2 Hz); MS for C₃₃H₃₆FN₃O₅ m/z 596.12 (M+Na)⁺.

Example 80 Compound 1532-((8-(3-(3,3-Dimethyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl2-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.175 g, 0.27 mmol) was added concentrated 4M HCl in dioxane (3.0 mL)and triethylsilane (0.02 mL). After stirring at room temperature for 3hours, the reaction mixture was concentrated in vacuo and lyophilized inacetonitrile:water (1:1) to obtain the title compound as a hydrochloridesalt (0.16 g, 96%); ¹H NMR (DMSO-d₆): δ 1.28 (s, 6H), 1.99-2.02 (m, 4H),2.53-2.67 (m, 2H), 3.17 (br, 2H), 3.44-3.72 (m, 4H), 3.75 (t, 2H, J=7.2Hz), 4.64 (s, 2H), 4.91 (s, 2H), 7.01-7.15 (m, 6H), 7.27 (dd, 1H, J=8and 1.2 Hz), 7.31 (d, 1H, J=7.2 Hz), 7.36 (d, 1H, J=7.2 Hz), 7.42 (t,1H, J=7.6 Hz), 7.57 (t, 1H, J=6.4 Hz), 7.92 (dd, 1H, J=8 and 1.2 Hz),9.93 (br, 1H), 13.18 (s, 1H); MS for C₃₄H₃₇FN₄O₄ m/z 585.11 (M+H)⁺.

Preparation of tert-butyl2-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of tert-butyl2-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.15 g, 0.34 mmol), sodium iodide (0.015 g, 0.1 mmol) and potassiumcarbonate (0.081 g, 0.51 mmol) in 2-butanone (4 mL), was added1-(3-chloropropyl)-3,3-dimethylindolin-2-one (0.081 g, 0.34 mmol). Afterstirring at 78° C. for 18 hours, the reaction mixture was filtered andisolated by Biotage flash chromatography (1-10%methanol/dichloromethane) and preparatory TLC (10%methanol/dichloromethane) to obtain the title compound (0.18 g, 83%); ¹HNMR (DMSO-d₆): δ 1.25 (s, 6H), 1.56 (s, 9H), 1.67-1.75 (m, 4H), 2.31(br, 4H), 2.64-2.66 (m, 4H), 3.72 (t, 2H, J=7.2

Hz), 4.58 (s, 2H), 4.82 (s, 2H), 6.90-6.91 (m, 2H), 7.02 (t, 1H, J=7.6Hz), 7.08-7.12 (m, 3H), 7.19-7.27 (m, 2H), 7.33 (d, 1H, J=6.8 Hz), 7.40(t, 1H, J=7.2 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.82 (dd, 1H, J=7.2 and 1.2Hz); MS for C₃₈H₄₅FN₄O₄ m/z 641.17 (M+H)⁺.

Example 81 Compound 1542-((4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of tert-butyl2-((4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(268 mg, 0.472 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 4 h. The mixture wasconcentrated in vacuo and purified using preparative thin layerchromatography in 7% methanol in dichloromethane. The pure extract wastreated with 4M hydrogen chloride solution in dioxane to afford thehydrogen chloride salt of the title compound as a white powder (80 mg,30%); ¹H NMR (400 MHz, DMSO-d₆): δ 2.01 (d, 2H, J=14.4 Hz); 2.09 (t, 2H,J=7.2 and 7.6 Hz); 3.02 (t, 2H, J=12.4 and 10.4 Hz); 3.18 (bs, 2H); 3.23(t, 2H, J=7.2 and 6.8 Hz); 3.65-3.7 (m, 4H); 4.69 (s, 2H); 4.94 (s, 2H);6.81 (t, 1H, J=7.2 and 7.6 Hz); 7.04 (d, 2H, J=8.4 Hz); 7.24 (t, 2H,J=7.6 and 8 Hz); 7.33 (d, 1H, J=8 Hz); 7.43 (t, 2H, J=7.6 Hz); 7.53-7.61(m, 3H); 7.66 (t, 1H, J=7.6 Hz); 7.93 (dd, 1H, J=1.2 and 1.6 Hz);7.99-8.01 (m, 2H); 10.5 (bs, 1H); 13.2 (bs, 1H); MS for C₃₁H₃₃N₃O₄ m/z512.4 (M+H)⁺.

Preparation of tert-butyl2-((4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (300mg, 0.72 mmol, 1 equiv), 4-iodo-1-phenylbutan-1-one (198.5 mg, 0.72mmol, 1 equiv) and potassium carbonate (199 mg, 1.44 mmol, 2 equiv) inN,N-dimethylformamide was stirred at 68° C. for 16 h. After cooling thereaction mixture, the crude mixture was partitioned between ethylacetate and water. The organic layer was dried over MgSO₄, filtered,concentrated, and the crude residue was purified using the preparativethin layer chromatography in 8% methanol in dichloromethane to affordthe title compound (268 mg, 65.5%); MS for C₃₅H₄₁N₃O₄ m/z 568.31 (M+H)⁺.

Preparation of 4-iodo-1-phenylbutan-1-one

Sodium iodide (1.64 g, 10.95 mmol, 2 equiv) was added to a solution of4-chloro-1-phenylbutan-1-one (1 g, 5.475 mmol, 1 equiv) in acetone. Thereaction mixture was refluxed for 16 h. After cooling to ambienttemperature, it was evaporated under reduced pressure to remove all theacetone. The residue was worked up using ethyl acetate and sodiumbisulfite, followed by a wash with brine. The organic layer was driedover MgSO₄, filtered and concentrated in vacuo. The crude residue waspurified using the Biotage flash chromatography system (SNAP 50 gcartridge, R_(f)=0.4, 5%-30% ethyl acetate in hexanes) to afford thetitle compound as white solid (880 mg, 59%). The bottle containing thecompound was wrapped in aluminium foil to stored in the freezer to avoidfurther darkening of the mixture; ¹H NMR (400 MHz, DMSO-d₆): δ 2.06-2.16(m, 2H); 3.14 (t, 2H, J=3.2 and 4 Hz); 3.34 (t, 2H, J=6.8 and 7.2 Hz);7.51-7.55 (m, 2H); 7.62-7.67 (m, 2H); 7.95-7.98 (m, 2H); MS for C₁₀H₁₁IOm/z 274.99 (M+H)⁺.

Example 82 Compound 1552-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of tert-butyl2-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(230 mg, 0.362 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 5 h. The mixture wasconcentrated in vacuo and purified using preparative thin layerchromatography in 10% methanol in dichloromethane. The pure extract wastreated with 4M hydrogen chloride solution in dioxane to afford thehydrogen chloride salt of the title compound as cream crystals (60 mg,28.8%); ¹H NMR (400 MHz, DMSO-d₆): δ 0.86-0.90 (m, 2H); 1.01-1.06 (m,2H); 1.98 (d, 2H, J=14.4 Hz); 2.13 (bs, 2H); 2.88-2.99 (m, 3H); 3.2 (bs,2H); 3.65-3.73 (m, 4H); 3.91 (t, 2H, J=6.8 Hz); 4.67 (s, 2H); 4.93 (s,2H); 6.80 (t, 1H, J=7.2 Hz); 7.01 (d, 2H, J=8.4 Hz); 7.08-7.10 (m, 2H);7.19-7.24 (m, 2H); 7.26-7.28 (m, 1H); 7.31 (d, 1H, J=7.6 Hz); 7.43 (t,1H, J=6.8 and 7.6 Hz); 7.55-7.59 (m, 1H); 7.92 (dd, 1H, J=1.2 Hz); 10.50(bs, 1H); 13.2 (bs, 1H); MS for C₃₄H₃₇N₅O₄ m/z 580.12 (M+H)⁺.

Preparation of tert-butyl2-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (200mg, 0.475 mmol, 1 equiv),1-(3-chloropropyl)-3-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (118.75mg, 0.475 mmol, 1 equiv), sodium iodide (28.5 mg, 0.19 mmol, 0.4 equiv)and potassium carbonate (131.3 mg, 0.95 mmol, 2 equiv) in 2-butanone wasstirred at 81° C. for 16 h. After cooling the reaction mixture, thecrude mixture was partitioned between ethyl acetate and water. Theorganic layer was dried over MgSO₄, filtered, concentrated, and thecrude residue was purified using the Biotage flash chromatography system(SNAP 10 g cartridge, R_(f)=0.5, gradient—1%-10% methanol indichloromethane) to afford the title compound (230 mg, 76%); ¹H NMR (400MHz, DMSO-d₆): δ 0.85-0.89 (m, 2H); 0.95-1.04 (m, 2H); 1.57 (s, 9H);1.67 (d, 2H, J=12.4 Hz); 1.81 (t, 2H, J=6.4 and 6.8 Hz); 2.32-2.35 (t,2H, J=6.8 Hz); 2.54-2.72 (m, 6H); 2.86-2.89 (m, 1H); 3.84-3.88 (t, 2H,J=6.8 and 6.4 Hz); 4.62 (s, 2H); 4.84 (s, 2H); 6.76-6.79 (t, 1H, J=7.2Hz); 6.84-6.86 (d, 2H, J=8.4 Hz); 7.03-7.06 (t, 2H, J=5.6 and 6.8 Hz);7.19-7.27 (m, 5H); 7.39-7.43 (t, 1H, J=7.6 and 7.2 Hz); 7.56-7.59 (t,1H, J=8 and 6.4 Hz); 7.82-7.84 (d, 1H, J=7.6 Hz); MS for C₃₈H₄₅N₅O₄ m/z636.12 (M+H)⁺.

Example 83 Compound 1563-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of tert-butyl3-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(166 mg, 0.254 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 5 h. The mixture wasconcentrated in vacuo and purified using preparative thin layerchromatography in 10% methanol in dichloromethane. The pure extract wastreated with 4M hydrogen chloride solution in dioxane to afford thehydrogen chloride salt of the title compound as cream crystals (55 mg,36.4%); ¹H NMR (400 MHz, DMSO-d₆): δ 0.86-0.90 (m, 2H); 1.01-1.06 (m,2H); 1.93 (d, 2H, J=14 Hz); 2.06-2.11 (m, 2H); 2.58-2.73 (m, 2H);2.88-2.89 (m, 1H); 3.19 (bs, 2H); 3.67-3.73 (m, 4H); 3.89 (t, 2H, J=6.8Hz); 4.62 (s, 4H); 7.05-7.12 (m, 6H); 7.22-7.27 (m, 2H); 7.48-7.57 (m,2H); 7.87-7.89 (m, 2H); 10.05 (bs, 1H); 13.03 (bs, 1H); MS forC₃₄H₃₆FN₅O₄ m/z 598.28 (M+H)⁺.

Preparation of tert-butyl3-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(163.5 mg, 0.372 mmol, 1 equiv),1-(3-chloropropyl)-3-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (93 mg,0.372 mmol, 1 equiv), sodium iodide (22.3 mg, 0.15 mmol, 0.4 equiv) andpotassium carbonate (102.8 mg, 0.74 mmol, 2 equiv) in 2-butanone wasstirred at 81° C. for 16 h. After cooling the reaction mixture, thecrude mixture was partitioned between ethyl acetate and water. Theorganic layer was dried over MgSO₄, filtered, concentrated, and thecrude residue was purified using the Biotage flash chromatography system(SNAP 10 g cartridge, R_(f)=0.5, gradient—1%-10% methanol indichloromethane) to afford the title compound (166 mg, 68%); MS forC₃₈H₄₄FN₅O₄ m/z 654.24 (M+H)⁺.

Example 84 Compound 1573-((8-(4-(4-fluorophenyl)-4-(methoxyimino)butyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, hydrochloride

tert-butyl3-((8-(4-(4-fluorophenyl)-4-(methoxyimino)butyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.28 g, 0.455 mmol) and formic acid (6 mL) were stirred at roomtemperature for 20 hours. The reaction was evaporated to dryness and theresidue purified by PTLC (10% methanol/dichloromethane) to give productas the formate salt; NMR (DMSO-d₆); δ1.62-1.69 (m, 4H); 2.51-2.62 (m,4H); 2.73-2.84 (m, 6H); 3.73 and 3.81 (E & Z isomers, s, 3H); 4.59 (s,2H); 4.61 (s, 2H); 6.75 (t, J=7.6 Hz, 1H); 6.83 (d, J=8.4 Hz, 2H);7.16-7.22 (m, 4H); 7.48-7.54 (m, 2H); 7.73-7.76 (m, 2H); 7.87-7.88 (m,2H); 8.17 (s, 1H). The formate salt was dissolved in 4M hydrochloricacid in dioxane (5 mL) and then evaporated under vacuum. The residue wasdissolved in acetonitrile (5 mL) and water (5 mL) and lyophilized togive product as a white solid (0.22 g, 82%); HPLC rt 11.89 min; NMR(DMSO-d₆); 61.90 (t, J=14.8 Hz, 2H); 2.07-2.12 (m, 1H); 2.78 (t, J=8 Hz,1H); 2.97-3.07 (m, 2H); 3.17-3.24 (m, 2H); 3.52-3.70 (m, 6H); 3.76 and3.94 (E & Z isomers, 3H); 4.64-4.66 (m, 4H); 6.79 (m, 1H); 7.03-7.09 (m,2H); 7.18-7.29 (m, 3H); 7.38 (t, J=8.8 Hz, 1H); 7.49-7.53 (m, 1H);7.56-7.59 (m, 1H); 7.75-7.79 (m, 1H); 7.88-7.90 (m, 2H); 8.06-8.10 (m,1H); 10.9 (br s, 1H); 13.3 (br s, 1H); MS for C₃₂H₃₅FN₄O₄ m/z 559(M+H)⁺.

Preparation of tert-butyl3-((8-(4-(4-fluorophenyl)-4-(methoxyimino)butyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

tert-Butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.25 g, 0.593 mmol), 1-(4-fluorophenyl)-4-iodobutan-1-one O-methyloxime (0.19 g, 0.593 mmol), and potassium carbonate (0.12 g, 0.890 mmol)in N,N-dimethylformamide (8 mL) were stirred at 65° C. for 2 hours. Thereaction was diluted with ethyl acetate, washed with water and brine,dried (MgSO₄), and evaporated. The residue was purified by PTLC (5%methanol/dichloromethane) to give product as an oil (0.28 g, 78%); MSfor C₃₆H₄₃FN₄O₄ m/z 615 (M+H)⁺.

Preparation of 1-(4-fluorophenyl)-4-iodobutan-1-one O-methyl oxime

4-Chloro-1-(4-fluorophenyl)butan-1-one O-methyl oxime (0.78 g, 3.40mmol) and sodium iodide (0.76 g, 5.09 mmol) in acetone (10 mL) wereheated at reflux overnight. The mixture was evaporated, the residuediluted with ethyl acetate, washed with water and brine, dried (MgSO₄)and evaporated. The residue was purified by Biotage flash columnchromatography (gradient to 10% ethyl acetate/hexanes) to give productas an oil (1.09 g, quant.); MS for C₁₁H₁₃FNO m/z 322 (M+H)⁺.

Preparation of 4-chloro-1-(4-fluorophenyl)butan-1-one O-methyl oxime

Methoxyamine hydrochloride (0.833 g, 9.97 mmol) was added portionwise to4-chloro-4′-fluorobutyrophenone (2.00 g, 9.97 mmol) in pyridine (10 mL)and the mixture stirred at room temperature overnight and evaporatedunder vacuum. The residue was diluted with ethyl acetate, washed with 2Naqueous hydrochloric acid and brine, dried (MgSO₄) and evaporated togive product as an oil (2.29 g, quant.); MS for C₁₁H₁₃ClFNO m/z 230(M+H)⁺.

Example 85 Compound 158

3-((1-(4-fluorophenyl)-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of tert-butyl3-((1-(4-fluorophenyl)-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(100 mg, 0.171 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 5 h. The mixture wasconcentrated in vacuo and purified using preparative thin layerchromatography in 10% methanol in dichloromethane to afford the titlecompound as white powder (25 mg, 23%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.62(d, 2H, J=14 Hz); 1.83 (t, 2H, J=6.8 and 7.2 Hz); 2.19-2.28 (m, 2H);2.44 (t, 2H, J=6.8 Hz); 2.78 (bs, 4H); 3.03 (t, 2H, J=7.2 and 6.8 Hz);4.54 (s, 2H); 4.59 (s, 2H); 6.81-6.85 (m, 2H); 6.99 (t, 2H, J=8.8 and9.6 Hz); 7.49-7.53 (m, 4H); 7.62 (t, 1H, J=7.6 Hz); 7.86 (bs, 2H);7.95-7.97 (m, 2H); 13.1 (bs, 1H); MS for C₃₁H₃₂FN₃O₄ m/z 530.4 (M+H)⁺.

Preparation of tert-butyl3-((1-(4-fluorophenyl)-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(250 mg, 0.57 mmol, 1 equiv), 4-chloro-1-phenylbutan-1-one (91.3 μl,0.57 mmol, 1 equiv), sodium iodide (34 mg, 0.23 mmol, 0.4 equiv) andpotassium carbonate (158 mg, 1.14 mmol, 2 equiv) in 2-butanone wasstirred at 81° C. for 16 h. After cooling, the reaction mixture wasfiltered, concentrated in vacuo and was purified using the Biotage flashchromatography system (SNAP 10 g cartridge, R_(f)=0.45, gradient—1%-10%methanol in dichloromethane) to afford the title compound (100 mg, 46%);¹H NMR (400 MHz, DMSO-d₆): δ 1.53 (s, 9H); 1.59-1.63 (m, 2H); 1.82 (t,2H, J=7.2 and 6.4 Hz); 2.19-2.23 (m, 2H); 2.37-2.39 (m, 2H); 2.70 (d,4H, J=7.2 Hz); 3.02 (t, 2H, J=6.8 and 6.4 Hz); 4.54 (s, 2H); 4.59 (s,2H); 6.84 (bs, 2H); 7.02 (t, 2H, J=9.6 and 8.8 Hz); 7.48-7.54 (m, 2H);7.63 (t, 1H, J=8 Hz); 7.79-7.84 (m, 2H); 7.95-7.98 (m, 2H); MS forC₃₅H₄₀FN₃O₄ m/z 586.5 (M+H)⁺.

Example 86 Compound 1592-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution of tert-butyl2-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(240 mg, 0.367 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 5 h. The mixture wasconcentrated in vacuo and purified using preparative thin layerchromatography in 10% methanol in dichloromethane to afford the titlecompound as a white powder (72 mg, 33%); ¹H NMR (400 MHz, DMSO-d₆): δ0.84-0.88 (m, 2H); 0.99-1.04 (m, 2H); 1.76 (d, 2H, J=13.6 Hz); 1.87 (bs,2H); 2.41 (bs, 2H); 2.84-2.88 (m, 1H); 3.85 (t, 2H, J=6.8 Hz); 4.60 (s,2H); 4.89 (s, 2H); 6.92-6.95 (m, 2H); 7.01-7.11 (m, 4H); 7.18-7.22 (m,2H); 7.28 (d, 1H, J=7.6 Hz); 7.40 (t, 1H, J=7.6 Hz); 7.57 (t, 1H, J=8and 7.2 Hz); 7.90 (d, 1H, J=6.8 Hz); 12.9 (bs, 1H); MS for C₃₄H₃₆FN₅O₄m/z 598.4 (M+H)⁺.

Preparation of tert-butyl2-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(163.5 mg, 0.372 mmol, 1 equiv),1-(3-chloropropyl)-3-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (93 mg,0.372 mmol, 1 equiv), sodium iodide (22.3 mg, 0.15 mmol, 0.4 equiv) andpotassium carbonate (102.8 mg, 0.74 mmol, 2 equiv) in 2-butanone wasstirred at 81° C. for 16 h. After cooling the reaction mixture, thecrude mixture was partitioned between ethyl acetate and water. Theorganic layer was dried over MgSO₄, filtered, concentrated, and thecrude residue was purified using preparative thin layer chromatographyto afford the title compound as a cream powder (240 mg, 65%); MS forC₃₈H₄₄FN₅O₄ m/z 654.34 (M+H)⁺.

Example 87 Compound 1603-((4-oxo-8-(3-(2-oxoindolin-3-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, hydrochloride

tert-Butyl3-((4-oxo-8-(3-(2-oxoindolin-3-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.29 g, 0.488 mmol) and 4M hydrochloric acid/1% triethylsilane in1,4-dioxane (6 mL) were stirred at room temperature for 4 hours. Thereaction was evaporated and the residue purified by PTLC (10%methanol/dichloromethane). The product obtained from PTLC wasredissolved in 4M hydrochloric acid in dioxane and evaporated. Theresidue was dissolved in acetonitrile (5 mL) and water (5 mL) andlyophilized to give product as a white solid (0.25 g, 90%); HPLC rt 9.32min; NMR (DMSO-d₆); δ1.82 (m, 4H); 1.89 (d, J=14 Hz, 2H); 2.94 (m, 2H);3.16 (m, 2H); 3.44-3.54 (m, 5H); 4.64 (s, 4H); 6.79 (t, J=7.2 Hz, 1H);6.84 (d, J=7.6 Hz, 1H); 6.97 (m, 1H); 7.01 (d, J=8.4 Hz, 2H); 7.17-7.23(m, 3H); 7.32 (d, J=7.6 Hz, 1H); 7.49-7.58 (m, 2H); 7.87-7.89 (m, 2H);10.38 (br s, 1H); 10.44 (s, 1H); 13.0 (br s, 1H); MS for C₃₂H₃₄N₄O₄ m/z539 (M+H)⁺.

Preparation of tert-butyl3-((4-oxo-8-(3-(2-oxoindolin-3-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

tert-Butyl3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.25 g, 0.593 mmol), 3-(2-oxoindolin-3-yl)propyl methanesulfonate (0.16g, 0.593 mmolmmol), sodium iodide (0.027 g, 0.178 mmol) and potassiumcarbonate (0.12 g, 0.890 mmol) in 2-butanone (8 mL) were stirred at 78°C. for 2 hours. The reaction was diluted with ethyl acetate, washed withwater and brine, dried (MgSO₄), and evaporated. The residue was purifiedby PTLC (5% methanol/dichloromethane) to give product as an oil (0.29 g,82%); MS for C₃₆H₄₂N₄O₄ m/z 595 (M+H)⁺.

3-(2-oxoindolin-3-yl)propyl methanesulfonate

Methanesulfonyl chloride (0.42 mL, 5.39 mmol) was added dropwise at 0°C. to 3-(3-hydroxypropyl)indolin-2-one (1.03 g, 5.39 mmol) andtriethylamine (1.13 mL, 8.09 mmol) in dichloromethane (20 mL). Themixture was allowed to warm to room temperature and stirred for 2 hours.The reaction was washed with 2M aqueous hydrochloric acid and brine,dried (MgSO₄), and evaporated. The residue was purified by Biotage flashcolumn chromatography (30% ethyl acetate/hexanes) to give product as anoil (1.45 g, quant.); ¹H NMR (DMSO-d₆); δ1.66-1.70 (m, 2H); 1.85-1.94(m, 2H); 3.15 (s, 3H); 3.48 (t, J=6.4 Hz, 1H); 4.19 (t, J=6.4 Hz, 2H);6.82 (d, J=8 Hz, 1H); 6.96 (m, 1H); 7.18 (m, 1H); 7.25 (d, J=7.6 Hz,1H); 10.4 (s, 1H); MS for C₁₂H₁₅NO₄S m/z 270 (M+H)⁺.

Preparation of 3-(3-hydroxypropyl)indolin-2-one

Lithium aluminum hydride (0.5M solution in diglyme, 13.8 mL, 6.9 mmol)was added dropwise at 0° C. to methyl 3-(2-oxoindolin-3-yl)propanoate(1.51 g, 6.90 mmol) in tetrahydrofuran (30 mL). The mixture was allowedto warm to room temperature and then quenched with 2N aqueoushydrochloric acid. The reaction was extracted with ethyl acetate. Theextract was washed with brine, dried (MgSO₄) and evaporated. The residuewas purified by Biotage flash column chromatography (50% ethylacetate/hexanes) to give product as a white solid (1.13 g, 86%); ¹H NMR(DMSO-d₆); δ1.38 (m, 2H); 1.85 (m, 2H); 3.32-3.38 (t, J=6.4 Hz, 1H);4.38 (t, J=5.2 Hz, 1H); 6.80 (d, J=8 Hz, 1H); 6.94 (m, 1H); 7.16 (m,1H); 7.22 (d, J=7.2 Hz, 1H); 10.3 (s, 2H)

Preparation of methyl 3-(2-oxoindolin-3-yl)propanoate

A mixture of methyl 3-indolepropionate (5.00 g, 0.0246 mol), acetic acid(10 mL), dimethylsulfoxide (26 mL, 0.369 mol, 15 eq.) and concentratedhydrogen chloride (37%) (22 mL, 0.738 mol, 30 eq.) was stirred atambient temperature for 2.5 h. Water was added to the mixture and themixture was extracted with ethyl acetate. The organic layer was driedover MgSO₄, filtered and concentrated in vacuo. The crude residue waspurified using the Biotage flash chromatography system (30% ethylacetate in hexanes) to afford the title compound as an oil (5.28 g,98%); ¹H NMR (DMSO-d₆); 62.03-2.10 (m, 2H); 2.32-2.39 (m, 2H); 3.46 (t,J=6.4 Hz, 1H); 3.54 (s, 3H); 6.81 (d, J=7.6 Hz, 1H); 6.93-6.97 (m, 1H);7.15-7.17 (m, 1H); 7.24 (d, J=7.6 Hz, 1H);

Example 88 Compound 1612-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl2-((1-(4-fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.12 g, 0.19 mmol) was added concentrated formic acid (2 mL) andtriethylsilane (0.05 mL). After stirring at room temperature for 18hours, the reaction mixture was concentrated, isolated by pTLC (10%methanol/dichloromethane) and lyophilized with 4M HCl in dioxane (0.5mL) to obtain the title compound as a hydrochloride salt (0.038 g, 33%);¹H NMR (DMSO-d₆): δ 1.53 (t, 2H, J=3.6 Hz), 1.61 (t, 2H, J=3.6 Hz), 2.00(d, 2H, J=14.4 Hz), 2.08 (t, 2H, J=8 Hz), 2.70 (t, 2H, J=13.6 Hz), 3.20(br, 2H), 3.45-3.72 (m, 4H), 3.83 (t, 2H, J=7.2 Hz), 4.64 (s, 2H), 4.91(s, 2H), 6.99-7.10 (m, 6H), 7.20-7.28 (m, 2H), 7.31 (d, 1H, J=7.6 Hz),7.42 (t, 1H, J=7.6 Hz), 7.59 (t, 1H, J=6.8 Hz), 7.91 (dd, 1H, J=7.6 and1.2 Hz), 10.26 (br, 1H), 13.18 (s, 1H); MS for C₃₄H₃₅FN₄O₄ m/z 583.3(M+H)⁺.

tert-Butyl2-((1-(4-fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of tert-butyl2-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.2 g, 0.46 mmol), sodium iodide (0.021 g, 0.14 mmol) and potassiumcarbonate (0.095 g, 0.7 mmol) in 2-butanone (5 mL), was added1′-(3-chloropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one (0.107 g,0.46 mmol). After stirring at 78° C. for 5 hours, the reaction mixturewas filtered and isolated by Biotage flash chromatography (1-10%methanol/dichloromethane) and preparatory TLC (10%methanol/dichloromethane) to obtain the title compound (0.13 g, 44%); ¹HNMR (DMSO-d₆): δ 1.50 (t, 2H, J=6.4 Hz), 1.56-1.60 (m, 11H), 1.69 (d,2H, J=9.2 Hz), 1.75 (t, 2H, J=6.4 Hz), 2.32-2.34 (m, 4H), 2.64-2.67 (m,4H), 3.79 (t, 2H, J=6.4 Hz), 4.58 (s, 2H), 4.82 (s, 2H), 6.91-6.92 (m,2H), 6.97-6.99 (m, 2H), 7.08-7.15 (m, 3H), 7.19 (d, 1H, J=6.8 Hz),7.25-7.31 (m, 1H), 7.41 (t, 1H, J=8 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.82(dd, 1H, J=8 and 1.2 Hz); MS for C₃₈H₄₃FN₄O₄ m/z 639.4 (M+H)⁺.

Example 89 Compound 1622-((8-(3-(3-Fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl2-((8-(3-(3-fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.1 g, 0.16 mmol) was added concentrated 4M HCl in dioxane (1.6 mL) andtriethylsilane (0.02 mL). After stirring at room temperature for 4hours, the reaction mixture was concentrated, isolated by preparatoryTLC (10% methanol/dichloromethane) and lyophilized with 4M HCl indioxane (1 mL) to obtain the title compound as a hydrochloride salt(0.039 g, 40%); ¹H NMR (DMSO-d₆): δ 1.72 (d, 3H, J=23.2 Hz), 1.97 (d,2H, J=14 Hz), 2.07 (br, 2H), 2.93 (t, 2H, J=10 Hz), 3.17 (br, 2H),3.44-3.79 (m, 8H), 4.64 (s, 2H), 4.92 (s, 2H), 6.80 (t, 1H, J=7.2 Hz),6.99 (d, 1H, J=8.4 Hz), 7.07 (d, 1H, J=8 Hz), 7.15 (t, 1H, J=7.6 Hz),7.20-7.26 (m, 2H), 7.31 (d, 1H, J=7.6 Hz), 7.40-7.48 (m, 2H), 7.57 (t,1H, J=7.6 Hz), 7.92 (dd, 1H, J=8 and 1.2 Hz), 10.27 (br, 1H), 13.21 (s,1H); MS for C₃₃H₃₅FN₄O₄ m/z 571.3 (M+H)⁺.

Preparation of tert-butyl2-((8-(3-(3-fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of tert-butyl2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.17 g, 0.4 mmol), sodium iodide (0.018 g, 0.12 mmol) and potassiumcarbonate (0.083 g, 0.6 mmol) in 2-butanone (4 mL), was added1-(3-chloropropyl)-3-fluoro-3-methylindolin-2-one (0.097 g, 0.4 mmol).After stirring at 78° C. for 5 hours, the reaction mixture was filteredand isolated by Biotage flash chromatography (1-10%methanol/dichloromethane) to obtain the title compound (0.11 g, 44%); ¹HNMR (DMSO-d₆): δ 1.57 (s, 9H), 1.65-1.72 (m, 5H), 1.79 (t, 2H, J=6.8Hz), 2.35 (t, 2H, J=6.4 Hz), 2.56-2.71 (m, 6H), 3.75 (t, 2H, J=6.4 Hz),4.61 (s, 2H), 4.84 (s, 2H), 6.76 (t, 1H, J=7.6 Hz), 6.84 (d, 2H, J=8Hz), 7.12 ((t, 1H, J=7.6 Hz), 7.21-7.26 (m, 4H), 7.38-7.42 (m, 2H), 7.57(t, 2H, J=6.4 Hz), 7.82 (dd, 1H, J=7.6 and 1.2 Hz); MS for C₃₇H₄₃FN₄O₄m/z 627.4 (M+H)⁺.

Example 90 Compound 1632-(((8-(3-(3-Fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl2-((8-(3-(3-fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.2 g, 0.31 mmol) was added concentrated 4M HCl in dioxane (3 mL) andtriethylsilane (0.05 mL). After stirring at room temperature for 4hours, the reaction mixture was concentrated, isolated by preparatoryTLC (10% methanol/dichloromethane) and lyophilized with 4M HCl indioxane (1 mL) to obtain the title compound as a hydrochloride salt(0.073 g, 38%); ¹H NMR (DMSO-d₆): δ 1.72 (d, 3H, J=23.2 Hz), 1.98-2.07(m, 4H), 2.72 (t, 2H, J=10 Hz), 3.18 (br, 2H), 3.45-3.72 (m, 4H), 3.76(t, 2H, J=6.8 Hz), 4.64 (s, 2H), 4.91 (s, 2H), 7.06-7.08 (m, 4H), 7.15(t, 1H, J=7.6 Hz), 7.24 (d, 1H, J=7.6 Hz), 7.31 (d, 1H, J=7.2 Hz),7.40-7.46 (m, 2H), 7.57 (t, 2H, J=7.6 Hz), 7.92 (d, 1H, J=8 Hz), 10.27(br, 1H), 13.21 (s, 1H); MS for C₃₃H₃₄F₂N₄O₄ m/z 589.3 (M+H)⁺.

Preparation of tert-butyl2-((8-(3-(3-fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of tert-butyl2-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.15 g, 0.34 mmol), sodium iodide (0.015 g, 0.1 mmol) and potassiumcarbonate (0.070 g, 0.51 mmol) in 2-butanone (5 mL), was added1-(3-chloropropyl)-3-fluoro-3-methylindolin-2-one (0.083 g, 0.34 mmol).After stirring at 78° C. for 18 hours, the reaction mixture was filteredand isolated by Biotage flash chromatography (1-10%methanol/dichloromethane) to obtain the title compound (0.2 g, 91%); ¹HNMR (DMSO-d₆): δ 1.56 (s, 9H), 1.65-1.71 (m, 5H), 1.77 (t, 2H, J=7.2Hz), 2.31-2.33 (m, 4H), 2.50-2.66 (m, 4H), 3.72 (t, 2H, J=6.8 Hz), 4.58(s, 2H), 4.82 (s, 2H), 6.88-6.91 (m, 2H), 7.08-7.12 (m, 3H), 7.18 (d,1H, J=8.4 Hz), 7.26 (d, 1H, J=7.6 Hz), 7.37-7.42 (m, 2H), 7.55-7.59 (m,2H), 7.82 (d, 1H, J=6.4 Hz); MS for C₃₇H₄₂F₂N₄O₄ m/z 645.3 (M+H)⁺.

Example 91 Compound 1643-((8-(3-(3-Fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

To tert-butyl3-((8-(3-(3-fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.26 g, 0.4 mmol) was added concentrated 4M HCl in dioxane (4 mL) andtriethylsilane (0.05 mL). After stirring at room temperature for 4hours, the reaction mixture was concentrated, isolated by preparatoryTLC (10% methanol/dichloromethane) and lyophilized with 4M HCl indioxane (1 mL) to obtain the title compound as a hydrochloride salt(0.16 g, 64%); ¹H NMR (DMSO-d₆): δ 1.72 (d, 3H, J=22.4 Hz), 1.92 (d, 2H,J=13.6 Hz), 2.06 (br, 2H), 2.67 (t, 2H, J=10 Hz), 3.19 (br, 2H),3.45-3.71 (m, 4H), 3.76 (t, 2H, J=7.2 Hz), 4.62 (s, 4H), 7.07 (d, 4H,J=6.4 Hz), 7.15 (t, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz), 7.44-7.59 (m,4H), 7.87 (dd, 2H, J=6.8 and 2 Hz), 10.27 (br, 1H), 13.03 (s, 1H); MSfor C₃₃H₃₄F₂N₄O₄ m/z 589.3 (M+H)⁺.

Preparation of tert-butyl3-((8-(3-(3-fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

To a solution of tert-butyl3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.2 g, 0.46 mmol), sodium iodide (0.021 g, 0.14 mmol) and potassiumbicarbonate (0.095 g, 0.69 mmol) in 2-butanone (5 mL), was added1-(3-chloropropyl)-3-fluoro-3-methylindolin-2-one (0.11 g, 0.46 mmol).After stirring at 78° C. for 2 hours, the reaction mixture was filteredand isolated by Biotage flash chromatography (1-10%methanol/dichloromethane) to obtain the title compound (0.27 g, 91%); ¹HNMR (DMSO-d₆): δ 1.52 (s, 9H), 1.65-1.71 (m, 5H), 1.77 (t, 2H, J=6.8Hz), 2.32-2.34 (m, 4H), 2.66-2.68 (m, 4H), 3.72 (t, 2H, J=6.8 Hz), 4.57(d, 4H, J=15.6 Hz), 6.88-6.91 (m, 2H), 7.07-7.13 (m, 3H), 7.18 (d, 1H,J=8 Hz), 7.39 (t, 1H, J=8 Hz), 7.47-7.56 (m, 3H), 7.78 (s, 1H), 7.82(dt, 1H, J=6.8 and 2 Hz); MS for C₃₇H₄₂F₂N₄O₄ m/z 645.5 (M+H)⁺.

Example 92 Compound 166(R)-2-(4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylaceticacid

A solution of (R)-tert-butyl2-(4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate(257 mg, 0.453 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 5 h. The mixture wasconcentrated in vacuo and purified using preparative thin layerchromatography in 10% methanol in dichloromethane. The purified mixturewas treated with 4M hydrogen chloride solution in dioxane to afford thehydrogen chloride salt of the title compound as a cream powder (100 mg,28%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.94 (m, 2H); 2.07 (m, 2H); 2.85 (m,2H); 3.14 (m, 2H); 3.49-3.52 (m, 4H); 3.76 (t, 2H, J=6.8 Hz); 4.17 (d,1H, J=5.2 Hz); 4.87 (d, 1H, J=4.8 Hz); 5.79 (s, 1H); 6.85 (m, 1H);6.97-7.04 (m, 3H); 7.12 (d, 1H, J=7.6 Hz); 7.21 (t, 1H, J=7.6 and 8.4Hz); 7.28 (dd, 2H, J=5.6 and 6 Hz); 7.42-7.45 (m, 6H) 10.6 (bs, 1H);13.4 (bs, 1H); MS for C₃₂H₃₄N₄O₄ m/z 539 (M+H)⁺.

Preparation of (R)-tert-butyl2-(4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate

A mixture of (R)-tert-butyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (250mg, 0.60 mmol, 1 equiv), 1-(3-chloropropyl)-3-methylindolin-2-one (125.8mg, 0.60 mmol, 1 equiv), sodium iodide (36 mg, 0.24 mmol, 0.4 equiv),and potassium carbonate (166 mg, 1.2 mmol, 2 equiv) in 2-butanone wasstirred at 81° C. for 16 h. After cooling the reaction mixture, thecrude mixture was partitioned between ethyl acetate and water. Theorganic layer was dried over MgSO₄, filtered, concentrated, and thecrude residue was purified using preparative thin layer chromatographyin 10% methanol in dichloromethane to afford the title compound as acream solid (100 mg, 28%); MS for C₃₆H₄₂N₄O₄ m/z 595.32 (M+H)⁺.

Example 93 Compound 167(R)-2-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylaceticacid

To (R)-tert-butyl2-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate(0.26 g, 0.4 mmol) was added concentrated 4M HCl in dioxane (4 mL).After stirring at room temperature for 18 hours, the reaction mixturewas filtered, washed with dichloromethane and dried to obtain the titlecompound as a hydrochloride salt (0.17 g, 78%); ¹H NMR (DMSO-d₆): δ 1.88(t, 2H, J=13.6 Hz), 2.06-2.10 (m, 2H), 2.92 (br, 2H), 3.18-3.24 (m, 4H),3.58 (br, 4H), 4.19 (d, 1H, J=4.8 Hz), 4.87 (d, 1H, J=4.8 Hz), 5.81 (s,1H), 6.83 (t, 1H, J=7.2 Hz), 7.00 (d, 2H, J=8 Hz), 7.22 (t, 2H, J=8.4Hz), 7.42-7.45 (m, 5H), 7.55 (t, 2H, J=7.6 Hz), 7.66 (t, 1H, J=7.2 Hz),7.99 (d, 2H, J=7.2 Hz), 10.47 (br, 1H), 13.54 (s, 1H); MS for C₃₁H₃₃N₃O₄m/z 512.3 (M+H)⁺.

Preparation of (R)-tert-butyl2-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate

To a solution of benzyl (R)-tert-butyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate(0.33 g, 0.78 mmol) and potassium carbonate (0.22 g, 1.56 mmol) inN,N-dimethylformamide (7.5 mL), was added 4-iodo-1-phenylbutan-1-one(0.22 g, 0.78 mmol). After stirring at 60° C. for 18 hours, the reactionmixture was diluted with ethyl acetate (25 mL), washed with water andbrine. The organic phase was dried over MgSO₄, filtered, and isolated bypreparatory TLC (8% methanol/dichloromethane) to obtain the titlecompound (0.23 g, 52%); ¹H NMR (DMSO-d₆): δ 1.42 (s, 9H), 1.55 (t, 2H,J=13.6 Hz), 1.82 (t, 2H, J=7.2 Hz), 2.31-2.40 (m, 4H), 2.50-2.72 (m,4H), 3.32 (t, 2H, J=7.6 Hz), 4.08 (d, 1H, J=4.8 Hz), 4.74 (d, 1H, J=4.8Hz), 5.75 (s, 1H), 6.72-6.79 (m, 3H), 7.14 (t, 2H, J=7.6 Hz), 7.34-7.47(m, 5H), 7.52 (t, 2H, J=7.6 Hz), 7.63 (t, 1H, J=7.2 Hz), 7.97 (d, 2H,J=7.2 Hz); MS for C₃₅H_(4i)N₃O₄ m/z 568.4 (M+H)⁺.

Example 94 Compound 168(S)-2-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylaceticacid

A solution of (R)-tert-butyl2-(4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate(257 mg, 0.453 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 5 h. The mixture wasconcentrated in vacuo and purified using preparative thin layerchromatography in 10% methanol in dichloromethane. The pure extract wastreated with 4M hydrogen chloride solution in dioxane to afford thehydrogen chloride salt of the title compound as a cream powder (100 mg,28%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.88 (m, 2H); 2.05-2.09 (m, 2H); 2.85(m, 2H); 3.15-3.24 (m, 2H); 3.56-3.59 (m, 4H); 4.19 (d, 1H, J=4.4 Hz);4.89 (d, 1H, J=4.8 Hz); 5.81 (s, 1H); 6.84 (m, 1H); 6.99 (d, 2H, J=8.4Hz); 7.23 (t, 2H, J=7.6 and 8.4 Hz); 7.45-7.47 (m, 5H); 7.55 (t, 2H,J=7.6 and 8 Hz); 7.64-7.68 (m, 1H); 7.98-8.01 (m, 2H); 10.4 (bs, 1H);13.5 (bs, 1H); MS for C₃₁H₃₃N₃O₄ m/z 512.4 (M+H)⁺.

Preparation of (S)-tert-butyl2-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate

A mixture of (S)-tert-butyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (300mg, 0.71 mmol, 1 equiv), 4-chloro-1-phenylbutan-1-one (130 mg, 0.71mmol, 1 equiv), sodium iodide (42.6 mg, 0.28 mmol, 0.4 equiv), andpotassium carbonate (196.3 mg, 1.42 mmol, 2 equiv) in 2-butanone wasstirred at 81° C. for 16 h. After cooling the reaction mixture, thecrude mixture was partitioned between ethyl acetate and water. Theorganic layer was dried over MgSO₄, filtered, concentrated, and thecrude residue was purified using the Biotage flash chromatography system(SNAP 10 g cartridge, R_(f)=0.5, gradient—1%-10% methanol indichloromethane) to afford the title compound as an oil (200 mg, 50%);MS for C₃₅H₄₁N₃O₄ m/z 568.4 (M+H)⁺.

Preparation of (S)-tert-butyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate

(R)-methyl 2-amino-2-phenylacetate (5 g, 24.8 mmol, 1 equiv) wasdissolved in a mixture of 48% hydrogen bromide (13 ml, 198 mmol, 8equiv) and water (19 ml). An aqueous solution of sodium nitrite (5.48 g,79.36 mmol, 3.2 equiv) was added slowly and the mixture stirred at 0° C.for 1.5 h. The reaction was degassed in vacuo and extracted with ether.The organic layer was further washed with water and brine, dried overMgSO₄, and concentrated in vacuo. The resulting residue was purifiedusing the Biotage flash chromatography system (SNAP 100 g cartridge,R_(f)=0.5, gradient—10% ethyl acetate/hexanes) to afford the (S)-methyl2-bromo-2-phenylacetate as a light yellow oil (2.3 g, 40% yield); ¹H NMR(400 MHz, DMSO-d₆): δ 3.72 (s, 3H); 5.95 (s, 1H); 7.36-7.42 (m, 3H);7.53 (d, 2H, J=1.2 Hz); 7.56 (d, 1H, J=2 Hz). MS for C₉H₉BrO₂ m/z 229.98(M+H)⁺.

A mixture of benzyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.4 g, 6.55mmol, 1 equiv), 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran(7.86 ml, 7.86 mmol, 1.2 equiv), and (S)-methyl 2-bromo-2-phenylacetate(1.5 g, 6.55 mmol, 1 equiv) in N,N-dimethylformamide was stirred for 16h at ambient temperature. Reaction was diluted with ethyl acetate andthe organic layer was washed with water and brine. The combined organiclayers were dried over MgSO₄ and concentrated in vacuo. The cruderesidue was purified using the Biotage flash chromatography system (SNAP100 g cartridge, R_(f)=0.4, gradient—10%-50% ethyl acetate in hexanes)to afford (S)-benzyl3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylatesan orange solid (2.11 g, 63%); MS for C₃₀H₃₁N₃O₅ m/z 514.23 (M+H)⁺.

A solution of (S)-benzyl3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(2.16 g, 4.21 mmol, 1 equiv.) and lithium hydroxide (353 mg, 8.41 mmol,2 equiv) in a 4:1 mixture of methanol and water (20 ml t/v) was stirredat ambient temperature for 16 hrs. The reaction was concentrated invacuo and the mixture was partitioned between ethyl acetate and 10%citric acid. The organic layer was further washed with water and brine,dried over MgSO₄, filtered and concentrated. The resulting residue wasdried thoroughly to afford(S)-2-(8-(benzyloxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylaceticacid as a white solid (2.05 g, quant); ¹H NMR (400 MHz, DMSO-d₆): δ 1.67(t, 2H, J=12.4 and 10.4 Hz); 2.25-2.33 (m, 2H); 3.56 (m, 2H); 3.98-4.05(m, 2H); 4.14 (d, 1H, J=4.4 Hz); 4.86 (d, 1H, J=5.2 Hz); 5.14 (m, 2H);5.81 (s, 1H); 6.67 (d, 2H, J=7.6 Hz); 6.81 (t, 1H, J=6.8 and 7.6 Hz);7.17 (dd, 2H, J=7.6 and 7.2 Hz); 7.32-7.45 (m, 10H); 13.5 (s, 1H); MSfor C₂₉H₂₉N₃O₅ m/z 500.21 (M+H)⁺.

(S)-2-(8-(benzyloxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylaceticacid (2.05 g, 4.1 mmol, 1 equiv) was suspended in toluene and themixture was heated to refluxing temperatures. N,N-dimethylformamidedi-tert-butyl acetal (3.94 ml, 16.44 mmol, 4 equiv) was added dropwiseto the refluxing mixture within 30 minutes. Refluxing was continued foran additional 30-45 minutes after which it was cooled and stirred atambient temperature for 16 h. The reaction was diluted with ethylacetate and the organic layer was washed with sodium bicarbonate (sat),water and brine. The ethyl acetate layer was dried over MgSO₄, filtered,concentrated in vacuo and purified using the Biotage flashchromatography system (SNAP 100 g cartridge, R_(f)=0.5, gradient—5%-30%ethyl acetate in hexanes) to afford the (S)-benzyl3-(2-tert-butoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(1.75 g, 77%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.43 (s, 9H); 1.60 (m, 2H);2.24-2.32 (m, 2H); 3.53 (bs, 2H); 3.96-4.05 (m, 2H); 4.11 (d, 1H, J=5.2Hz); 4.77 (d, 1H, J=5.2 Hz); 5.13 (bs, 2H); 5.69 (s, 1H); 6.68 (d, 2H,J=8.4 Hz); 6.82 (t, 1H, J=7.2 Hz); 7.22 (dd, 2H, J=7.6 Hz); 7.32-7.46(m, 10H); MS for C₃₃H₃₇N₃O₅ m/z 556.28 (M+H)⁺.

A solution of (S)-benzyl3-(2-tert-butoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(1.88 g, 3.39 mmol, 1 equiv) in a mixture of ethyl acetate and ethanolwas charged with 10% palladium on carbon (1 g, 20%/wt) and the resultingmixture was hydrogenated at atmospheric pressure for 2 h. The reactionwas filtered over Celite and the filtrate was concentrated and dried invacuo to afford the title compound as a dark grey foam (1.24 g, 93%); MSfor C₂₅H₃₁N₃O₃ m/z 422.24 (M+H)⁺.

Example 95 Compound 170(S)-2-(4-oxo-8-(3-(2-Oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylaceticacid

To a solution of benzyl (S)-tert-butyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (0.2g, 0.48 mmol), sodium iodide (0.022 g, 0.14 mmol) and potassiumcarbonate (0.1 g, 0.72 mmol) in 2-butanone (5 mL), was added1-(3-chloropropyl)indolin-2-one (0.101 g, 0.48 mmol). After stirring at78° C. for 2 hours, the reaction mixture was filtered and isolated byBiotage flash chromatography (1-10% methanol/dichloromethane) andpreparatory TLC (10% methanol/dichloromethane) to obtain (S)-tert-butyl2-(4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate(0.07 g, 25%).

To (S)-tert-butyl2-(4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate(0.07 g, 0.12 mmol) was added concentrated 4M HCl in dioxane (1.5 mL)and triethylsilane (0.015 mL). After stirring at room temperature for 5hours, the reaction mixture was concentrated, purified by reverse phaseHPLC and lyophilized with 4M HCl in dioxane (1 mL) to obtain the titlecompound as a hydrochloride salt (0.015 g, 22%); ¹H NMR (DMSO-d₆): δ1.86 (t, 2H, J=12 Hz), 2.09 (br, 2H), 2.77 (br, 2H), 3.19 (br, 2H),3.45-3.57 (m, 6H), 3.76 (t, 2H, J=6.8 Hz), 4.17 (d, 1H, J=4.8 Hz), 4.86(d, 1H, J=4.8 Hz), 5.78 (s, 1H), 6.83 (t, 1H, J=7.6 Hz), 6.94 (d, 2H,J=8.4 Hz), 7.02 (t, 1H, J=7.6 Hz), 7.11 (d, 1H, J=8.4 Hz), 7.22 (t, 2H,J=8 Hz), 7.28 (t, 2H, J=6.8 Hz), 7.40-7.46 (m, 5H), 10.08 (br, 1H),13.50 (s, 1H); MS for C₃₂H₃₄N₄O₄ m/z 539.4 (M+H)⁺.

Example 96 Compound 1714-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, hydrochloride

tert-Butyl4-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.30 g, 0.482 mmol) and formic acid (6 mL) were stirred at roomtemperature for 20 hours. The reaction was evaporated to dryness and theresidue purified by PTLC (10% methanol/dichloromethane). The product wasdissolved in 4M hydrochloric acid in 1,4-dioxane (5 mL) and thenevaporated under vacuum. The residue was dissolved in acetonitrile (5mL) and water (5 mL) and lyophilized to give product as a white solid(0.21, 72%); HPLC rt 11.01 min; ¹H NMR (DMSO-d₆); δ1.29 (s, 6H); 1.93(d, J=14 Hz, 2H); 2.08-2.13 (m, 2H); 2.93-3.02 (m, 2H); 3.16-3.20 (m,2H); 3.46-3.71 (m, 4H); 3.77 (t, J=7.2 Hz, 2H); 4.64 (s, 2H); 4.65 (s,2H); 6.79 (t, J=7.2 Hz, 1H); 7.03-7.08 (m, 3H); 7.17-7.22 (m, 3H);7.26-7.30 (m, 1H); 7.36-7.38 (m, 1H); 7.43 (d, J=8.4 Hz, 2H); 7.94 (m,2H); 10.7 (br s, 1H); MS for C₃₄H₃₈N₄O₄ m/z 567 (M+H)⁺.

Preparation of tert-butyl4-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

tert-Butyl4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.25 g, 0.593 mmol), 1-(3-chloropropyl)-3,3-dimethylindolin-2-one (0.14g, 0.593 mmol), sodium iodide (0.026 g, 0.18 mmol), and potassiumcarbonate (0.12 g, 0.890 mmol) in 2-butanone (8 mL) were heated at 78°C. for 4 hours. The reaction was diluted with 10%methanol/dichloromethane, filtered, and evaporated. The residue waspurified by PTLC (5% methanol/dichloromethane) to give product as an oil(0.31 g, 85%); MS for C₃₈H₄₆N₄O₄ m/z 623 (M+H)⁺.

Preparation of tert-butyl4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

Benzyl3-(4-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(4.90 g, 8.82 mmol) and palladium on carbon (10 wt. %, wet, Degussa typeE101 NE/W,) in ethyl acetate (50 mL) and methanol (50 mL) was stirred atroom temperature under hydrogen (balloon) for 3 hours. The catalyst wasremoved by filtration and the filtrate evaporated and dried under vacuumto give product as foam (3.70 g, 99%); ¹H NMR (DMSO-d₆); δ1.53 (s, 9H);2.35-2.48 (m, 2H); 2.85-2.92 (m, 2H); 3.17-3.23 (m, 2H); 3.23-3.43 (m,2H); 4.58 (s, 2H), 4.62 (s, 2H); 6.74 (t, J=6.8 Hz, 1H); 6.87 (d, J=8.4Hz, 2H); 7.20 (dd, J=7.6 Hz and 8.8 Hz, 2H); 7.40 (d, J=8.4 Hz, 2H);7.90 (m, 2H); MS for C₂₅H₃₁N₃O₃ m/z 422 (M+H)⁺.

Preparation of benzyl3-(4-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

Sodium hydride (60% dispersion in oil, 0.46 g, 0.0114 mol) was addedportionwise at 0° C. to benzyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (4.00 g,0.0109 mol) in N,N-dimethylformamide (40 mL) and the mixture stirred at0° C. for 10 minutes. tert-Butyl 4-(bromomethyl)benzoate (3.27 g, 0.0120mol) was added dropwise at 0° C., the mixture then allowed to warm toroom temperature, and stirred for 2 hours. The reaction was quenchedwith 2M aqueous hydrochloric acid and extracted with ethyl acetate. Theethyl acetate extracts were washed with brine, dried (MgSO₄), andevaporated. The residue was purified by Biotage flash columnchromatography (gradient 0 to 30% ethyl acetate/hexanes) to give productas an oil (4.97 g, 82%); ¹H NMR (DMSO-d₆); δ1.53 (s, 9H); 1.72 (d,J=13.6 Hz, 2H); 2.34-2.42 (m, 2H); 3.57 (m, 2H); 3.99-4.03 (m, 2H); 4.61(s, 2H); 4.63 (s, 2H); 6.69 (d, J=8 Hz, 2H); 6.78 (t, J=7.2 Hz, 1H);7.18 (dd, J=7.2 Hz and 8.8 Hz, 2H); 7.32-7.39 (m, 5H); 7.42 (d, J=8.4Hz, 2H); 7.90 (d, J=8.4 Hz, 2H);

Preparation of tert-Butyl 3-(bromomethyl)benzoate

tert-butyl 4-methylbenzoate (31 g, 0.161 mol), N-bromosuccinimide (31.5g, 0.177 mol), and benzoyl peroxide (0.39 g, 0.00161 mol) in carbontetrachloride (200 mL) were heated at reflux for 20 hours. The mixturewas allowed to cool to room temperature and succinimide filtered. Thefiltrate was evaporated and the residue purified by Biotage flashchromatography (gradient to 5% ethyl acetate/hexanes) to give product asan oil (27 g, 62%); NMR (DMSO-d₆); δ1.55 (s, 9H); 4.78 (s, 2H);7.47-7.51 (m, 1H); 7.68-7.71 (m, 1H); 7.82-7.85 (m, 1H); 7.97 (t, J=1.6Hz, 1H).

Preparation of tert-butyl 4-methylbenzoate

Lithium tert-butoxide (1M in hexanes, 178 mL, 0.178 mol) was addeddropwise at room temperature to p-toluoyl chloride (25 g, 0.162 mol) intetrahydrofuran (150 mL). The mixture was stirred at room temperatureovernight and then diluted with water and extracted with ethyl acetate.The extract was washed with brine, dried (MgSO₄), and evaporated to giveproduct as an oil which crystallized on standing (31 g, 98%)

Example 97 Compound 1724-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, hydrochloride

tert-butyl4-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.088 g, 0.148 mmol) and formic acid (6 mL) were stirred at roomtemperature for 20 hours. The reaction was evaporated to dryness and theresidue purified by PTLC (10% methanol/dichloromethane). The product wasdissolved in 4M hydrochloric acid in 1,4-dioxane (5 mL) and thenevaporated under vacuum. The residue was dissolved in acetonitrile (5mL) and water (5 mL) and lyophilized to give product as a white solid(0.051 g, 60%); ¹H NMR (DMSO-d₆); δ1.92 (d, J=15.2 Hz, 2H); 2.05-2.15(m, 2H); 2.95-3.01 (m, 2H); 3.15-3.25 (m, 2H); 3.46-3.70 (m, 4H); 3.57(s, 2H); 3.77 (t, J=7.2 Hz, 2H); 4.64 (s, 2H); 4.65 (s, 2H); 6.79 (t,J=7.6 Hz, 1H); 7.01-7.05 (m, 3H); 7.12-7.14 (m, 1H); 7.18-7.22 (m, 2H);7.26-7.30 (m, 2H); 7.43 (d, J=8.4 Hz, 2H); 7.93 (m, 2H); 10.8 (br s,1H); MS for C₃₂H₃₄N₄O₄ m/z 539 (M+H)⁺.

Preparation of tert-butyl4-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

tert-Butyl4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.25 g, 0.593 mmol), 1-(3-chloropropyl)indolin-2-one (0.12 g, 0.593mmol), sodium iodide (0.026 g, 0.18 mmol), and potassium carbonate (0.12g, 0.890 mmol) in 2-butanone (8 mL) were heated at 78° C. for 4 hours.The reaction was diluted with 10% methanol/dichloromethane, filtered,and evaporated. The residue was purified by PTLC (5%methanol/dichloromethane) to give product as an oil (0.088 g, 25%); MSfor C₃₆H₄₂N₄O₄ m/z 595 (M+H)⁺.

Example 98 Compound 1733-((8-(4-hydroxy-4-phenylbutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

A solution tert-butyl3-((8-(4-hydroxy-4-phenylbutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(300 mg, 0.527 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 5 h. The mixture wasconcentrated in vacuo and purified using preparative high performanceliquid chromatography to afford the acetate salt of the title compoundas a white solid (120 mg, 44.4%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.38-1.52(m. 2H); 1.60 (d, 2H, J=13.2 Hz); 1.84-1.94 (m, 2H); 2.41 (t, 2H, J=7.2and 7.6 Hz); 2.53-2.59 (m, 2H); 2.69-2.75 (m, 4H); 4.58 (s, 2H); 4.61(s, 2H); 5.84 (t, 1H, J=6.8 and 6.4 Hz); 6.74 (t, 1H, J=7.6 and 7.2 Hz);6.81 (s, 1H); 6.83 (s, 1H); 7.16-7.20 (m, 2H); 7.31-7.38 (m, 5H);7.48-754 (m, 2H); 7.86-7.88 (m, 2H); 8.30 (S, 1H); 12.8 (bs, 1H); MS forC₃₁H₃₅N₃O₄ m/z 514.4 (M+H)⁺.

Preparation of tert-butyl3-((8-(4-hydroxy-4-phenylbutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

A mixture of tert-butyl3-((4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(1.45 g, 2.56 mmol, 1 equiv) in ethanol was warmed to 41° C. Sodiumborohydride (194 mg, 5.13 mmol, 2 equiv) was slowly added and thereaction stirred as such for 30 minutes. It was stirred at roomtemperature for 16 h. The reaction was concentrated in vacuo and themixture was partitioned between ethyl acetate and water, followed by abrine wash. The organic layer was dried over MgSO₄, filtered andconcentrated. The residue was purified using the Biotage flashchromatography system (SNAP 50 g cartridge, R_(f)=0.45, gradient—1%-10%methanol in dichloromethane) to afford the title compound as a creamsolid (1.2 g, 83%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.52 (s, 9H); 1.59-1.66(m. 5H); 2.33-2.34 (m, 2H); 2.51-2.52 (m, 2H); 2.68-2.73 (m, 4H);4.57-4.61 (m, 5H); 5.51 (d, 1H, J=3.6 Hz); 6.74-6.77 (m, 1H); 6.82 (s,2H); 6.85 (s, 1H); 7.18-7.23 (m, 3H); 7.29-7.36 (m, 4H); 7.5-7.53 (m,2H); 7.79 (bs, 1H); 7.82-7.84 (m, 1H); MS for C₃₅H₄₃N₃O₄ m/z 570.33(M+H)⁺.

Example 99 Compound 1763-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, hydrochloride

tert-Butyl3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.28 g, 0.488 mmol) and formic acid (6 mL) were stirred at roomtemperature for 20 hours. The reaction was evaporated to dryness and theresidue purified by PTLC (10% methanol/dichloromethane). The product wasdissolved in 4M hydrochloric acid in 1,4-dioxane (5 mL) and thenevaporated under vacuum. The residue was dissolved in acetonitrile (5mL) and water (5 mL) and lyophilized to give product as a white solid(0.18 g, 65%); ¹H NMR (DMSO-d₆); δ1.05 (t, J=14.4 Hz, 2H); 1.20-1.40 (m,4H); 1.45-1.63 (m, 2H); 1.63-1.78 (m, 3H); 1.83-1.98 (m, 2H); 1.98-2.10(m, 3H); 2.20-2.40 (m, 2H); 3.12-3.17 (m, 2H); 3.19-3.24 (m, 2H);3.45-3.55 (m, 2H); 4.19 (s, 2H); 4.52 (s, 2H); 7.48-7.57 (m, 4H);7.64-7.68 (m, 1H); 7.85-7.89 (m, 2H); 7.98 (d, J=1.2 Hz, 1H); 8.00 (m,1H); 10.9 (br s, 1H); MS for C₃₁H₃₉N₃O₄ m/z 518 (M+H)⁺.

Preparation of tert-butyl3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

tert-Butyl3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.30 g, 0.585 mmol), 4-iodobutyrophenone (0.17 g, 0.585 mmol), andpotassium carbonate (0.12 g, 0.878 mmol) in N,N-dimethylformamide (8 mL)were stirred at 65° C. for 2 hours. The reaction was diluted with ethylacetate, washed with water and brine, dried (MgSO₄), and evaporated. Theresidue was purified by PTLC (5% methanol/dichloromethane) to giveproduct as an oil (0.28 g, 82%); MS for C₃₅H₄₇N₃O₄ m/z 574 (M+H)⁺.

Example 100 Compound 1773-(4-Cho-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoicacid

To a solution of methyl3-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate(0.08 g, 0.16 mmol) in methanol (3 mL) was added lithium hydroxidemonohydrate (0.013 g, 0.32 mmol) in water (1 mL). After stirring at 55°C. for 18 h, the reaction mixture was concentrated in vacuo, isolated bypreparatory TLC (10% methanol/dichloromethane/0.1% acetic acid) andlyophilized with 4M HCl/dioxane (0.5 mL) to obtain the title compound asa hydrochloride salt (0.011 g, 13%); ¹H NMR (DMSO-d₆): δ 2.07-2.16 (m,4H), 2.91 (br, 2H), 3.21-3.24 (m, 4H), 3.56-3.62 (m, 4H), 5.25 (s, 2H),6.90 (t, 1H, J=7.2 Hz), 7.24-7.34 (m, 4H), 7.53-7.68 (m, 4H), 7.81 (d,1H, J=7.6 Hz), 7.92 (dd, 1H, J=8 and 1.6 Hz), 8.00 (d, 2H, J=8 Hz), 8.69(s, 1H), 10.29 (br, 1H), 13.18 (br, 1H); MS for C₃₀H₃₁N₃O₄ m/z 498(M+H)⁺.

Example 101 Compound 179 Methyl3-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate

To a solution of benzyl3-(3-(methoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.18 g, 0.36 mmol) in methanol (4 mL), was added 10 wt % palladium oncarbon (0.036 g). After stirring under hydrogen at room temperature andatmospheric pressure for 18 hours, the reaction mixture was filtered,washed with methanol, concentrated in vacuo to obtain methyl3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (0.12 g).

To a solution of methyl3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (0.12 g,0.33 mmol) and potassium carbonate (0.091 g, 0.66 mmol) inN,N-dimethylformamide (3 mL), was added 4-iodo-1-phenylbutan-1-one (0.09g, 0.33 mmol). After stirring at 55° C. for 18 hours, the reactionmixture was diluted with ethyl acetate (50 mL), washed with water andbrine. The organic phase was dried over MgSO₄, filtered, and isolated byBiotage flash chromatography (1-8% methanol/dichloromethane) to obtainthe title compound (0.11 g, 65%); ¹H NMR (DMSO-d₆): δ 1.75 (d, 2H,J=10.8 Hz), 1.83 (t, 2H, J=7.2 Hz), 2.35-2.41 (m, 4H), 2.67-2.74 (m,4H), 3.04 (t, 2H, J=7.2 Hz), 3.88 (s, 3H), 5.19 (s, 2H), 6.87 (t, 1H,J=7.6 Hz), 7.02 (d, 2H, J=8 Hz), 7.24 (t, 2H, J=8.4 Hz), 7.52 (t, 2H,J=7.2 Hz), 7.57-7.65 (m, 2H), 7.79 (dt, 1H, J=8 and 1.2 Hz), 7.90-7.99(m, 3H), 8.58 (t, 1H, J=1.6 Hz); MS for C₃₁H₃₃N₃O₄ m/z 512.3 (M+H)⁺.

Preparation of benzyl3-(3-(methoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of benzyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.2 g, 0.55mmol), copper iodide (0.01 g, 0.055 mmol), N—N′-dimethylethylenediamine(0.012 mL, 0.11 mmol, d=0.819) and potassium carbonate (0.15 g, 1.1mmol) in acetonitrile (5 mL), was added methyl 3-iodobenzoate (0.143 g,0.55 mmol). After stirring at 75° C. for 18 hours, the reaction mixturewas diluted with ethyl acetate (50 mL), washed with dilute citric acid,water and brine. The organic phase was dried over MgSO₄, filtered, andisolated by Biotage flash chromatography (10-75% ethyl acetate/hexanes)to obtain the title compound (0.15 g, 55%); ¹H NMR (DMSO-d₆): δ 1.90 (d,2H, J=14 Hz), 2.26-2.34 (m, 2H), 3.56 (br, 2H), 3.88 (s, 3H), 4.00 (d,2H, J=12.8 Hz), 5.14-5.15 (m, 2H), 5.23 (s, 2H), 6.90 (t, 1H, J=7.2 Hz),6.96 (d, 2H, J=8 Hz), 7.27 (t, 2H, J=8 Hz), 7.30-7.38 (m, 5H), 7.61 (t,1H, J=8 Hz), 7.81 (dt, 1H, J=8.4 and 1.6 Hz), 7.93 (d, 1H, J=8.4 Hz),8.58 (t, 1H, J=2 Hz).

Example 102 Compound 1802-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoicacid

A solution of tert-butyl2-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate(410 mg, 0.741 mmol, 1 equiv) in 4M hydrogen chloride solution indioxane was stirred at ambient temperature for 5 h. The mixture wasconcentrated in vacuo and purified using preparative thin layerchromatography in 10% methanol in dichloromethane. The isolated mixturewas treated with 4M hydrogen chloride solution in dioxane to afford thehydrogen chloride salt of the title compound as a white powder (160 mg,43.5%); ¹H NMR (400 MHz, DMSO-d₆): δ 2.05-2.08 (m, 4H); 3.04 (m, 2H);3.16 (m, 2H); 3.22 (t, 2H, J=6.8 and 7.4 Hz); 3.56-3.71 (m, 4H); 5.10(s, 2H); 6.84 (t, 1H, J=7.2 Hz); 7.14 (s, 1H); 7.16 (s, 1H); 7.25-7.29(m, 2H); 7.52-7.57 (m, 3H); 7.63-7.68 (m, 2H); 7.71-7.75 (m, 1H); 7.94(dd, 1H, J=1.2 Hz); 7.98-8.00 (m, 2H); 10.61 (bs, 1H); 13.22 (bs, 1H);MS for C₃₀H₃₁N₃O₄ m/z 498.3 (M+H)⁺.

Preparation of tert-butyl2-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate

A mixture of tert-butyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (370 mg,0.909 mmol, 1 equiv), 4-iodo-1-phenylbutan-1-one (250 mg, 0.909 mmol, 1equiv) and potassium carbonate (251 mg, 1.82 mmol, 2 equiv) inN,N-dimethylformamide was stirred at 68° C. for 16 h. After cooling thereaction mixture, the crude mixture was partitioned between ethylacetate and water. The organic layer was dried over MgSO₄, filtered,concentrated, and the crude residue was purified using the Biotage flashchromatography system (SNAP 50 g cartridge, R_(f)=0.5, gradient—1%-10%methanol in dichloromethane) to afford the title compound as a whitepowder (410 mg, 82%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.49 (s, 9H);1.74-1.83 (m, 4H); 2.37 (t, 2H, J=7.2 Hz); 2.61 (t, 2H, J=10 and 11.2Hz); 2.726-2.73 (m, 4H); 3.05 (t, 2H, J=6.8 and 7.2 Hz); 5.06 (s, 2H);6.79 (t, 1H, J=7.2 and 7.6 Hz); 6.87 (s, 1H); 6.89 (s, 1H); 7.20 (m,2H); 7.46-7.69 (m, 6H); 7.76-7.78 (m, 1H); 7.95-7.99 (m, 2H); MS forC₃₄H₃₉N₃O₄ m/z 554.3 (M+H)⁺.

Preparation of tert-butyl2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate

A solution of benzyl3-(2-(tert-butoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(1.86 g, 3.44 mmol, 1 equiv) in a mixture of ethyl acetate and ethanolwas charged with 10% palladium on carbon (360 mg, 20%/wt) and theresulting mixture was hydrogenated at atmospheric pressure for 16 h. Thereaction was filtered over Celite and the filtrate was concentrated anddried in vacuo to afford the title compound as a white foam (1.44 g,96.4%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.49 (s, 9H); 1.71 (d, 2H, J=13.2Hz); 2.41-2.49 (m, 2H); 2.84-2.88 (m, 2H); 3.08-3.13 (m, 2H); 5.07 (s,2H); 6.78 (t, 1H, J=7.2 and 7.6 Hz); 6.98 (s, 1H); 7.00 (s, 1H);7.23-7.27 (m, 2H); 7.46-7.49 (m, 1H); 7.60 (dd, 1H, J=1.2 and 1.6 Hz);7.65-7.69 (m, 1H); 7.77 (dd, 1H, J=1.2 and 1.6 Hz); MS for C₂₄H₂₉N₃O₃m/z 408.22 (M+H)⁺.

Preparation of benzyl3-(2-(tert-butoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

2-(8-(benzyloxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoicacid (2.28 g, 4.69 mmol, 1 equiv) was suspended in toluene and themixture was heated to refluxing temperatures. N,N-dimethylformamidedi-tert-butyl acetal (4.5 ml, 18.76 mmol, 4 equiv) was added dropwise tothe refluxing mixture within 30 minutes. Refluxing was continued for anadditional 30-45 minutes after which it was cooled and stirred atambient temperature for 16 h. The reaction was diluted with ethylacetate and the organic layer was washed with sodium bicarbonate (sat),water and brine. The ethyl acetate layer was dried over MgSO₄, filtered,concentrated in vacuo and purified using the Biotage flashchromatography system (SNAP 100 g cartridge, R_(f)=0.5, gradient—5%-25%ethyl acetate in hexanes) to afford the title compound as a white solid(1.86 g, 73.3%); MS for C₃₂H₃₅N₃O₅ m/z 542.26 (M+H)⁺.

Preparation of2-(8-(benzyloxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoicacid

A solution of benzyl3-(2-(methoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(2.35 g, 4.7 mmol, 1 equiv.) and lithium hydroxide (394.4 mg, 9.4 mmol,2 equiv) in a 3:1 mixture of methanol and water (20 ml t/v) was stirredat 60° C. for 16 hrs. Some dioxane was added to remove the turbidity inthe reaction mixture and the stirring was continued for another 20 h.The reaction was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and 10% citric acid. The organic layer was washedwith water and brine, dried over MgSO₄, filtered and concentrated anddried in vacuo to afford the title compound as a cream solid (2.28 g,quant); ¹H NMR (400 MHz, DMSO-d₆): δ 1.88 (d, 2H, J=14 Hz); 2.38-2.45(m, 2H); 3.52 (bs, 2H); 3.97-4.05 (m, 2H); 5.08 (s, 2H); 5.15 (d, 2H,J=16.4 Hz); 6.79-6.84 (m, 3H); 7.20-7.24 (m, 2H); 7.33-7.39 (m, 5H);7.49-7.53 (m, 1H); 7.61 (dd, 1H, J=0.8 Hz); 7.68-7.72 (m, 1H); 791 (dd,1H, J=1.6 Hz); 13.1 (bs, 1H); MS for C₂₈H₂₇N₃O₅ m/z 486.3 (M+H)⁺.

Preparation of benzyl3-(2-(methoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

A mixture of benzyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.79 g, 7.63mmol, 1 equiv), methyl 2-iodobenzoate (2 g, 7.63 mmol, 1 equiv)potassium carbonate (2.11 g, 15.26 mmol, 2 equiv), copper(II) iodide(145.32 mg, 0.763 mmol, 0.1 equiv) and N,N′-dimethyl ethylenediamine(164.25 μl, 1.526 mmol, 0.2 equiv) in acetonitrile was heated at 75° C.for 16 h. Upon cooling 10% citric acid was added and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over MgSO4, filtered and concentrated. The residue waspurified using the Biotage flash chromatography system (SNAP 100 gcartridge, R_(f)=0.3, gradient—5%-30% ethyl acetate in hexanes) toafford the title compound as a white powder (2.35 g, 61.57%); ¹H NMR(400 MHz, DMSO-d₆): δ 1.85 (d, 2H, J=14 Hz); 2.35-2.51 (m, 2H); 3.49(bs, 2H); 3.98-4.03 (m, 2H); 5.14 (s, 2H); 6.84-6.87 (m, 3H); 7.22-7.26(m, 2H); 7.32-7.39 (m, 5H); 7.49-7.53 (m, 1H); 7.65 (dd, 1H, J=1.6 and1.2 Hz); 7.70-7.75 (m, 1H); 7.86 (dd, 1H, J=1.2 and 1.6 Hz); MS forC₂₉H₂₉N₃O₅ m/z 500.21 (M+H)⁺.

Example 103 Compound 1824-(4-Cho-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoicacid, hydrochloride

tert-Butyl4-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate(0.30 g, 0.542 mmol) and formic acid (6 mL) were stirred at roomtemperature for 20 hours. The reaction was evaporated to dryness and theresidue purified by PTLC (10% methanol/dichloromethane). The product wasdissolved in 4M hydrochloric acid in 1,4-dioxane (5 mL) and thenevaporated under vacuum. The residue was dissolved in acetonitrile (5mL) and water (5 mL) and lyophilized to give product as a white solid(0.19 g, 65%); HPLC rt 10.37 min; ¹H NMR (DMSO-d₆); δ2.11-2.15 (m, 4H);3.01 (m, 2H); 3.15-3.20 (m, 2H); 3.24 (t, J=7.2 hz, 2H); 3.46-3.49 (m,2H); 3.56-3.71 (m, 2H); 5.26 (s, 2H); 6.90 (m, 1H); 7.29-7.31 (m, 4H);7.55 (t, J=8 hz, 2H); 7.65 (t, J=7.2 hz, 1H); 7.99-8.04 (m, 6H); 10.83(br s, 1H); 12.98 (br s, 1H); MS for C₃₀H₃₁N₃O₄ m/z 498 (M+H)⁺.

Preparation of tert-butyl4-(4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate

tert-Butyl 4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate(0.274 g, 0.672 mmol), 4-iodobutyrophenone (0.18 g, 0.672 mmol), andpotassium carbonate (0.14 g, 1.01 mmol) in N,N-dimethylformamide (5 mL)were heated at 65° C. for 3 hours. The reaction was diluted with ethylacetate, washed with water and brine, dried (MgSO₄), and evaporated. Theresidue was purified by PTLC (5% methanol/dichloromethane) to giveproduct as an oil (0.30 g, 80%); MS for C₃₄H₃₉N₃O₄ m/z 554 (M+H)⁺.

Preparation of tert-butyl4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate

Benzyl3-(4-(tert-butoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.62 g, 1.14 mmol) and palladium on carbon (10 wt. %, wet, Degussa typeE101 NE/W,) (0.12 g) in ethyl acetate (5 mL) and methanol (5 mL) wasstirred at room temperature under hydrogen (balloon) for 3 hours. Thecatalyst was removed by filtration and the filtrate evaporated and driedunder vacuum to give product as foam (0.46 g, quant.); MS for C₂₄H₂₉N₃O₃m/z 408 (M+H)⁺.

Preparation of benzyl3-(4-(tert-butoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

N,N-Dimethylformamide di-tert-butyl acetal (1.39 mL, 5.79 mmol) wasadded slowly dropwise to4-(8-(benzyloxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoicacid (0.703 g, 1.45 mmol) in toluene (10 mL) at reflux. The reaction washeated at reflux for 30 minutes and then evaporated under vacuum. Theresidue was purified by PTLC (30% ethyl acetate/hexanes) to give productas an oil (0.62 g, 79%); ¹H NMR (DMSO-d₆); δ1.55 (s, 9H); 1.90 (d, 14.4Hz, 2H); 2.24-2.32 (m, 2H); 3.55 (m, 2H); 3.98-4.03 (m, 2H); 5.14 (m,2H); 5.22 (s, 2H); 6.92 (t, J=7.2 Hz, 1H), 6.97 (d, J=7.6 Hz, 2H); 7.28(m, 2H); 7.33-7.38 (m, 5H); 7.96 (s, 4H); MS for C₃₂H₃₅N₃O₅ m/z 542(M+H)⁺.

Preparation of4-(8-(benzyloxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-ylbenzoicacid

Benzyl3-(4-(methoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(1.16 g, 2.32 mmol) and lithium hydroxide (0.15 g, 3.48 mmol) inmethanol (10 mL) and water (1 mL) were stirred at 45° C. for 20 h. Thereaction was partially evaporated under vacuum, the residue acidifiedwith 6M hydrochloric acid, and extracted with ethyl acetate. The extractwas washed with brine, dried (MgSO₄), and evaporated to give product asa white solid (1.13 g, quant.); ¹H NMR (DMSO-d₆); δ1.89 (d, J=14 Hz,2H); 2.27-2.33 (m, 2H); 3.56 (m, 2H); 3.98-4.01 (m, 2H); 5.14 (d, 13.6Hz, 2H); 5.23 (s, 2H); 6.91 (t, J=7.6 Hz, 1H); 6.96 (d, J=8 Hz, 2H);7.27 (dd, J=7.6 Hz and 8.8 Hz, 2H); 7.32-7.38 (m, 5H); 7.96-8.02 (m,4H); 12.9 (br s, 1H); MS for C₂₈H₂₇N₃O₅ m/z 486 (M+H)⁺.

Preparation of benzyl3-(4-(methoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

Benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.50g, 1.37 mmol), methyl 4-fluorobenzoate (0.21 g, 1.37 mmol), andpotassium carbonate (0.38 g, 2.74 mmol) in dimethyl sulfoxide werestirred at 100° C. for 3 days. The reaction was diluted with ethylacetate, washed with water and brine, dried (MgSO₄), and evaporated. Theresidue was purified by Biotage flash chromatography (gradient from 0 to30% ethyl acetate/hexanes) to give product as an oil (0.68 g, 21%); ¹HNMR (DMSO-d₆); δ1.90 (d, 15.6 hz, 2H); 2.25-2.34 (m, 2H); 3.56 (m, 2H);3.98-4.02 (m, 2H); 5.13 (m, 2H); 5.24 (s, 2H); 6.92 (t, J=8.4 hz, 1H);6.98 (d, J=8.8 hz, 2H); 7.26-7.39 (m, 7H); 8.02 (dd, J=10 Hz and 17.6Hz, 4H); MS for C₂₉H₂₉N₃O₅ m/z 500 (M+H)⁺.

Example 104 Compound 186N-(4-((4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide

N-(4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decanyl)methyl)phenyl)methanesulfonamide,hydrochloride salt (0.35 g, 0.776 mmol), 4-iodobutyrophenone (0.21 g,0.776 mmol), and potassium carbonate (0.21 g, 1.55 mmol) inN,N-dimethylformamide (10 mL) were stirred at 65° C. for 2 hours. Thereaction was diluted with ethyl acetate, washed with water and brine,dried (MgSO₄), and evaporated. The residue was purified by PTLC (5%methanol/dichloromethane) to give product as a white solid (0.36 g,82%); HPLC rt 12.97 min; ¹H NMR (DMSO-d₆); δ1.58 (d, J=11.2 Hz, 2H);1.85 (t, J=6 Hz, 2H); 2.44 (m, 4H); 2.73-2.76 (m, 4H); 2.97 (s, 3H);3.06 (t, J=6.8 Hz, 2H); 4.49 (s, 2H); 4.55 (s, 2H); 6.72-6.77 (m, 3H);7.13-7.26 (m, 6H); 7.51-7.55 (m, 2H); 7.62-7.66 (m, 1H); 7.98-8.00 (m,2H); 9.75 (br s, 1H); MS for C₃₁H₃₆N₄O₄S m/z 561 (M+H)⁺.

Preparation ofN-(4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide,hydrochloride salt

tert-Butyl3-(4-(methylsulfonamido)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(2.30 g, 4.47 mmol) and 4M hydrochloric acid in 1,4-dioxane (25 mL) werestirred at room temperature for 2 hours. The reaction was evaporated anddried under vacuum to give product as a light yellow solid (2.02 g,quant.); MS for C₂₁H₂₆N₄O₃S m/z 415 (M+H)⁺.

Preparation of tert-butyl3-(4-(methylsulfonamido)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

Methanesulfonyl chloride (0.39 mL, 5.02 mmol) was added dropwise at 0°C. to tert-butyl3-(4-aminobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(2.19 g, 5.02 mmol) and pyridine (0.61 mL, 7.53 mmol) in dichloromethane(10 mL). The reaction was allowed to warm to room temperature andstirred for 30 minutes. The mixture was diluted with dichloromethane,washed with 2M aqueous hydrochloric acid and brine, dried (MgSO₄) andevaporated. The residue was purified by PTLC (50% ethyl acetate/hexanes)to give product as an oil (2.38 g, 92%); ¹H NMR (DMSO-d₆); δ1.45 (s,9H); 1.63 (d, J=14 Hz, 2H); 2.18-2.23 (m, 2H); 2.98 (s, 3H); 3.30-3.55(m, 2H); 3.80-3.95 (m, 2H); 4.52 (s, 2H); 4.59 (s, 2H); 6.67 (d, J=8 Hz,2H); 6.76 (t, J=7.2 Hz, 2H); 7.15-7.21 (m, 4H); 7.26-7.28 (m, 2H); MSfor C₂₆H₃₄N₄O₅S m/z 515 (M+H)⁺.

Preparation of tert-butyl3-(4-aminobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

tert-Butyl3-(4-nitrobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(2.59 g, 5.55 mmol) and palladium on carbon (10 wt. %, wet, Degussa typeE101 NE/W) (0.52 g) in ethyl acetate (30 mL) was stirred at roomtemperature under hydrogen (balloon) for 3 hours. The catalyst wasremoved by filtration and the filtrate evaporated and dried under vacuumto give product as an oil (2.42 g, quant.); ¹H NMR (DMSO-d₆); δ1.45 (s,9H); 1.57 (d, J=14 Hz, 2H); 2.39 (m, 2H); 3.45 (m, 2H); 3.88 (m, 2H);4.36 (s, 2H); 4.52 (s, 2H); 5.09 (s, 2H); 6.53 (m, 2H); 6.64 (d, J=8 Hz,2H); 6.75 (t, J=7.6 Hz, 1H); 6.96 (d, J=8.4 Hz, 2H); 7.16 (dd, J=7.2 Hzand 8.8 Hz, 2H); MS for C₂₅H₃₂N₄O₃ m/z 437 (M+H)⁺.

Preparation of tert-butyl3-(4-nitrobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

tert-Butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(2.00 g, 6.03 mmol), 4-nitrobenzyl bromide (1.30 g, 6.03 mmol), andpotassium carbonate (1.25 g, 9.05 mmol) in N,N-dimethylformamide (20 mL)were heated at 65° C. for 4 hours. The reaction was diluted with ethylacetate, washed with water and brine, dried (MgSO₄), and evaporated. Theresidue was purified by PTLC (50% ethyl acetate/hexanes) to give productas a light yellow solid (2.59, 92%); ¹H NMR (DMSO-d₆); δ1.46 (s, 9H);1.68 (d, J=13.6 Hz, 2H); 2.42 (m, 2H); 3.42 (m, 2H); 3.89 (m, 2H); 4.66(s, 2H); 4.71 (s, 2H); 6.69 (d, J=8.4 Hz, 2H); 6.78 (t, J=6.8 Hz, 1H);7.19 (dd, J=7.2 Hz and 8.8 Hz, 2H); 7.58 (d, J=8.8 Hz, 2H); 8.24 (m,2H); MS for C₂₅H₃₀N₄O₅ m/z 467 (M+H)⁺.

Example 105 Compound 211N-(3-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide

To a solution of3-(3-aminophenyl)-8-(4-(4-fluorophenyl)-4-oxobutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one(200 mg, 0.416 mmol, 1 equiv) in dichloromethane, maintained at 0° C.,pyridine (66.6 μl, 0.823 mmol, 2 equiv) followed by the addition ofmethanesulfonyl chloride (28.7 μl, 0.3704 mmol, 0.9 equiv). The reactionwas slowly warmed to room temperature and stirred for 16 h. It wasdiluted with dichloromethane and the organic layer was washed with 10%,citric acid followed by a brine wash. The organic layer was dried overMgSO₄, filtered and concentrated in vacuo. The residue was purifiedusing preparatory thin layer chromatography in 7% methanol indichloromethane to afford the title compound as a white powder (40 mg,17%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.77 (bs, 2H); 1.85 (bs, 2H);2.32-2.33 (m, 4H); 2.67-2.73 (m, 4H); 3.02 (s, 3H); 3.04 (m, 2H); 5.12(s, 2H); 6.89 (dd, 1H, J=7.6 and 7.2 Hz); 7.02 (bs, 2H); 7.06-708 (m,1H); 7.25-7.29 (m, 2H); 7.32-7.41 (m, 4H); 7.90-7.91 (m, 1H); 8.04-8.07(m, 2H); 9.83 (s, 1H); MS for C₃₀H₃₃FN₄O₄S m/z 565.3 (M+H)⁺.

Example 106 Compound 212N-(3-((4-Oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide

To a solution of benzyl3-(3-(methylsulfonamido)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.82 g, 1.49 mmol) in methanol (15 mL), was added 10 wt % palladium oncarbon (0.15 g). After stirring under hydrogen at room temperature andatmospheric pressure for 18 hours, the reaction mixture was filtered,washed with methanol, concentrated in vacuo to obtainN-(3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide(0.62 g, 99%).

To a solution ofN-(3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide(0.2 g, 0.48 mmol), sodium iodide (0.029 g, 0.19 mmol) and potassiumcarbonate (0.133 g, 0.96 mmol) in 2-butanone (5 mL), was added1′-(3-chloropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one (0.114 g,0.48 mmol). After stirring at 78° C. for 18 hours, the reaction mixturewas filtered and isolated by preparatory TLC (10%methanol/dichloromethane) to obtain the title compound (0.09 g, 31%); ¹HNMR (DMSO-d₆): δ 1.51 (t, 2H, J=3.6 Hz), 1.58 (t, 2H, J=3.6 Hz), 1.64(d, 2H, J=13.2 Hz), 1.80 (br, 2H), 2.37 (br, 2H), 2.51-2.57 (m, 2H),2.68-2.73 (m, 4H), 2.96 (s, 3H), 3.82 (t, 2H, J=6.8 Hz), 4.52 (s, 2H),4.58 (s, 2H), 6.76 (t, 1H, J=7.6 Hz), 6.84 (d, 2H, J=8.4 Hz), 6.96-7.02(m, 3H), 7.09 (s, 1H), 7.12 (d, 1H, J=8 Hz), 7.17-7.24 (m, 4H), 7.32 (t,1H, J=8 Hz), 9.81 (s, 1H); MS for C₃₄H₃₉N₅O₄S m/z 614.4 (M+H)⁺.

Preparation of benzyl3-(3-(methylsulfonamido)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a refluxing solution of benzyl3-(3-nitrobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.77 g, 1.53 mmol) and ammonium chloride (0.96 g, 18.0 mmol) in 2:1mixture of ethanol/water (18 mL), was added iron powder (0.3 g, 5.4mmol) over a period of 45 minutes. After refluxing for another hour, thereaction mixture was extracted with dichloromethane, washed the organicextracts with water and brine. The organic phase was dried over MgSO₄and concentrated to obtain benzyl3-(3-aminobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.80 g, 95%). To a cooled (0° C.) solution of benzyl3-(3-nitrobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.8 g, 1.7 mmol) and pyridine (0.275 mL, 3.4 mmol, d=0.978) indichloromethane (20 mL), was added methanesulfonyl chloride (0.12 mL,1.53 mmol, d=1.48). After stirring at room temperature for 18 hours, thereaction mixture was washed with dilute citric acid, water and brine.The organic phase was dried over MgSO₄, filtered, and isolated byBiotage flash chromatography (10-100% ethyl acetate/hexanes) to obtainthe title compound (0.83 g, 89%); ¹H NMR (DMSO-d₆): δ 1.73 (d, 2H,J=13.6 Hz), 2.35-2.43 (m, 2H), 2.97 (s, 3H), 3.57 (br, 2H), 4.00-4.05(m, 2H), 4.55 (s, 2H), 4.61 (s, 2H), 5.13 (br, 2H), 6.88 (d, 2H, J=8Hz), 6.76 (t, 1H, J=7.6 Hz), 7.03 (d, 1H, J=7.6 Hz), 7.10-7.20 (m, 4H),7.31-7.39 (m, 6H), 9.80 (s, 1H); MS for C₂₉H₃₂N₄O₅S m/z 549.3 (M+H)⁺.

Preparation of benzyl3-(3-nitrobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a solution of benzyl4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1 g, 2.74mmol) and potassium carbonate (0.76 g, 5.48 mmol) inN,N-dimethylformamide (25 mL), was added 3-nitrobenzyl bromide (0.59 g,2.74 mmol). After stirring at 65° C. for 18 hours, the reaction mixturewas diluted with ethyl acetate (200 mL), washed with dilute citric acid,water and brine. The organic phase was dried over MgSO₄, filtered, andisolated by Biotage flash chromatography (10-100% ethyl acetate/hexanes)to obtain the title compound (0.9 g, 66%); ¹H NMR (DMSO-d₆): δ 1.73 (d,2H, J=14 Hz), 2.35-2.40 (m, 2H), 3.57 (br, 2H), 4.02 (dd, 2H, J=8 and3.6 Hz), 4.65 (s, 2H), 4.71 (s, 2H), 5.12-5.15 (m, 2H), 6.70 (d, 2H,J=8.4 Hz), 6.76 (t, 1H, J=7.2 Hz), 7.17 (t, 2H, J=8 Hz), 7.32-7.35 (m,5H), 7.66-7.70 (m, 1H), 7.76 (d, 1H, J=8 Hz), 8.16-8.18 (m, 2H). MS forC₂₈H₂₈N₄O₅ m/z 501.3 (M+H)⁺.

Example 107 Compound 213N-(3-((4-Cho-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide

To a solution ofN-(3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide(0.22 g, 0.53 mmol), sodium iodide (0.032 g, 0.21 mmol) and potassiumcarbonate (0.146 g, 1.06 mmol) in 2-butanone (5 mL), was added1-(3-chloropropyl)indolin-2-one (0.11 g, 0.53 mmol). After stirring at78° C. for 3 hours, the reaction mixture was filtered and isolated bypreparatory TLC (10% methanol/dichloromethane) to obtain the titlecompound (0.041 g, 13%); ¹H NMR (DMSO-d₆): δ 1.66 (d, 2H, J=13.6 Hz),1.78 (t, 2H, J=6.8 Hz), 2.33-2.47 (m, 2H), 2.50-2.56 (m, 2H), 2.76 (br,4H), 2.96 (s, 3H), 3.54 (s, 2H), 3.73 (t, 2H, J=6.8 Hz), 4.52 (s, 2H),4.58 (s, 2H), 6.77 (t, 1H, J=7.2 Hz), 6.85 (d, 2H, J=8.4 Hz), 6.97-7.02(m, 2H), 7.08-7.13 (m, 3H), 7.20-7.26 (m, 4H), 7.32 (t, 1H, J=8 Hz),9.80 (s, 1H); MS for C₃₂H₃₇N₅O₄S m/z 588.3 (M+H)⁺.

Example 108 Compound 214N-(4-(8-(4-(4-Fluorophenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)phenyl)methanesulfonamide

To tert-butyl3-(4-(methylsulfonamido)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.91 g, 1.82 mmol) was added 4M solution of HCl in dioxane (10 mL).After stirring at room temperature for 18 hours, the reaction mixturewas concentrated in vacuo to obtainN-(4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)phenyl)methanesulfonamideas a hydrochloride salt (0.7 g).

To a solution ofN-(4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)phenyl)methanesulfonamide(0.2 g, 0.46 mmol) and potassium carbonate (0.191 g, 1.38 mmol) inN,N-dimethylformamide (5 mL), was added1-(4-fluorophenyl)-4-iodobutan-1-one (0.134 g, 0.46 mmol). Afterstirring at 65° C. for 18 hours, the reaction mixture was diluted withethyl acetate (25 mL), washed with water and brine. The organic phasewas dried over MgSO₄, filtered, concentrated and isolated by pTLC (10%methanol/dichloromethane) to obtain the product (0.03 g, 12%); ¹H NMR(DMSO-d₆): δ 1.70-1.90 (m, 4H), 2.40-2.49 (m, 2H), 2.66-2.84 (m, 6H),2.97 (s, 3H), 3.05 (br, 2H), 5.12 (s, 2H), 6.88 (t, 1H, J=7.6 Hz)6.99-7.03 (m, 2H), 7.26 (d, 4H, J=9.2 Hz), 7.34 (t, 2H, J=8.4 Hz), 7.76(d, 2H, J=8.8 Hz), 8.04-8.07 (m, 2H), 9.73 (s, 1H); MS for C₃₀H₃₃FN₄O₄Sm/z 565.3 (M+H)⁺.

Preparation of tert-butyl3-(4-methylsulfonamido)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate

To a refluxing solution of tert-butyl3-(4-nitrophenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(1.0 g, 2.2 mmol) and ammonium chloride (1.18 g, 22.0 mmol) in 2:1mixture of ethanol/water (21 mL), was added iron powder (0.37 g, 6.6mmol) over a period of 45 minutes. After refluxing for another hour, thereaction mixture was extracted with dichloromethane, washed the organicextracts with water and brine. The organic phase was dried over MgSO₄and concentrated to obtain tert-butyl3-(4-aminophenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.9 g, 97%).

To a cooled (0° C.) solution of tert-butyl3-(4-aminophenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate(0.9 g, 1.99 mmol) and pyridine (0.322 mL, 3.98 mmol, d=0.978) indichloromethane (20 mL), was added methanesulfonyl chloride (0.138 mL,1.79 mmol, d=1.48). After stirring at room temperature for 18 hours, thereaction mixture was washed with dilute citric acid, water and brine.The organic phase was dried over MgSO₄, filtered, and isolated byBiotage flash chromatography (10-100% ethyl acetate/hexanes) to obtainthe title compound (0.92 g, 92%); ¹H NMR (DMSO-d₆): δ 1.45 (s, 9H), 1.78(d, 2H, J=14 Hz), 2.32 (t, 2H, J=12.4 Hz), 2.97 (s, 3H), 3.44 (br, 2H),3.87 (br, 2H), 5.15 (s, 2H), 6.87-6.91 (m, 3H), 7.24-7.28 (m, 4H), 7.78(d, 2H, J=8.8 Hz), 9.73 (s, 1H); MS for C₂₅H₃₂N₄O₅S m/z 501.3 (M+H)⁺.

Example 109 Compound 215N-(4-(4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)phenyl)methanesulfonamide

N-(4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decanyl)methyl)phenyl)methanesulfonamide,hydrochloride salt (0.30 g, 0.665 mmol),),1-(3-chloropropyl)indolin-2-one (0.14 g, 0.665 mmol), sodium iodide(0.030 g, 0.2 mmol), and potassium carbonate (0.14 g, 0.998 mmol) in2-butanone (10 mL) were heated at 78° C. for 4 hours. The reaction wasdiluted with 10% methanol/dichloromethane, filtered, and evaporated. Theresidue was purified by PTLC (5% methanol/dichloromethane) to giveproduct as a white solid (0.095 g, 25%); HPLC rt 11.99 min; ¹H NMR(DMSO-d₆); δ1.95 (d, J=14.8 hz, 2H); 2.03 (m, 2H); 2.73 (m, 2H); 2.97(s, 3H); 3.24 (m, 2H); 3.53-3.62 (m, 4H); 3.58 (s, 2H); 3.77 (t, J=6.8hz, 2H); 4.51 (s, 2H); 4.61 (s, 2H); 6.83 (t, J=7.6 hz, 1H); 6.91 (d,J=8.4 hz, 2H); 7.04 (t, J=7.6 hz, 1H); 7.11 (d, J=8 hz, 1H); 7.18-7.29(m, 8H); 9.78 (s, 1H); MS for C₃₁H₃₅N₅O₄S m/z 574 (M+H)⁺.

Example 110 Compound 216N-(4-(4-Oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)phenyl)methanesulfonamide

N-(4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decanyl)methyl)phenyl)methanesulfonamide,hydrochloride salt (0.30 g, 0.665 mmol),1′-(3-chloropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one) (0.16 g,0.665 mol), sodium iodide (0.030 g, 0.2 mmol), and potassium carbonate(0.14 g, 0.998 mmol) in 2-butanone (10 mL) were heated at 78° C. for 4hours. The reaction was diluted with 10% methanol/dichloromethane,filtered, and evaporated. The residue was purified by PTLC (5%methanol/dichloromethane) to give product as a white solid (0.32 g,80%); HPLC rt 13.43 min; ¹H NMR (DMSO-d₆); δ1.54 (m, 2H); 1.63 (m, 2H);1.95 (d, J=14.8 hz, 2H); 2.07 (m, 2H); 2.74 (m, 2H); 2.97 (s, 3H); 3.25(m, 2H); 3.56-3.66 (m, 4H); 3.85 (t, J=6.8 hz, 2H); 4.52 (s, 2H); 4.61(s, 2H); 6.83 (t, J=7.2 hz, 1H); 6.91 (d, J=8 hz, 2H); 7.01-7.06 (m,2H); 7.18-7.29 (m, 8H); 9.78 (s, 1H); MS for C₃₃H₃₇N₅O₄S m/z 600 (M+H)⁺.

Example 111 Compound 217N-(4-(8-(3-(3,3-Dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)phenyl)methanesulfonamide

N-(4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decanyl)methyl)phenyl)methanesulfonamide,hydrochloride salt (0.30 g, 0.665 mmol),1-(3-chloropropyl)-3,3-dimethylindolin-2-one (0.16 g, 0.665 mmol),sodium iodide (0.030 g, 0.2 mmol), and potassium carbonate (0.14 g,0.998 mmol) in 2-butanone (10 mL) were heated at 78° C. for 4 hours. Thereaction was diluted with 10% methanol/dichloromethane, filtered, andevaporated. The residue was purified by PTLC (5%methanol/dichloromethane) to give product as a white solid (0.31 g,78%); HPLC rt 14.12 min; ¹H NMR (DMSO-d₆); δ1.27 (s, 6H), MS forC₃₃H₃₉N₅O₄S m/z 602 (M+H)⁺.

Example 112 Compound 2182-((1-Cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, hydrochloride

tert-Butyl2-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.22 g, 0.383 mmol) and formic acid (6 mL) were stirred at roomtemperature for 20 hours. The reaction was evaporated to dryness and theresidue purified by PTLC (10% methanol/dichloromethane). The product wasdissolved in 4M hydrochloric acid in 1,4-dioxane (5 mL) and thenevaporated under vacuum. The residue was dissolved in acetonitrile (5mL) and water (5 mL) and lyophilized to give product as a white solid(0.15 g, 70%); ¹H NMR (DMSO-d₆); δ1.08 (t, J=14.4 Hz, 2H); 1.20-1.30 (m,2H); 1.33-1.68 (m, 5H); 1.74 (d, J=12.4 Hz, 2H); 2.07 (m, 3H); 2.54 (m,2H); 3.11-3.16 (m, 3H); 3.23 (t, J=6.8 Hz, 2H); 4.59 (s, 2H); 4.84 (s,2H); 7.42 (m, 2H); 7.52-7.59 (m, 3H); 7.65 (m, 1H); 7.92 (d, J=7.2 Hz,1H); 7.99 (dd, J=1.2 and 8 Hz, 2H); 11.0 (br s, 1H); 13.2 (br s, 1H); MSfor C₃₁H₃₉N₃O₄ m/z 518 (M+H)⁺.

Preparation of tert-Butyl2-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate

tert-Butyl2-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate(0.30 g, 0.585 mmol), 4-iodobutyrophenone (0.17 g, 0.585 mmol), andpotassium carbonate (0.12 g, 0.878 mmol) in N,N-dimethylformamide (8 mL)were stirred at 65° C. for 2 hours. The reaction was diluted with ethylacetate, washed with water and brine, dried (MgSO₄), and evaporated. Theresidue was purified by PTLC (5% methanol/dichloromethane) to giveproduct as an oil (0.22 g, 65%); MS for C₃₅H₄₇N₃O₄ m/z 574 (M+H)⁺.

1. A compound of formula: I

or a pharmaceutically acceptable salt thereof, or isomer thereof,wherein R₁ is chosen from the group consisting of(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)(C₂-C₄alkyl) optionallysubstituted at the 3 position with cyclopropyl or at the 6 position withchlorine, (2-oxobenzo[d]oxazol-3(2H)-yl)(C₂-C₄alkyl),(2-oxobenzo[d]thiazol-3(2H)-yl)(C₂-C₄alkyl),(2-oxoindolin-1-yl)(C₂-C₄alkyl) optionally substituted at the 3-positionwith one or two components chosen from methyl or fluoro,(3-spirocyclopropane-(2-oxoindolin-1-yl))(C₂-C₄alkyl),(2-oxoindolin-3-yl))(C₂-C₄alkyl),bis(4-fluorophenyl)methyl-(C₁-C₆alkyl),(1H-benzo[d][1,2,3]triazol-1-yl)(C₂-C₄alkyl),2,3-dihydrobenzo[b][1,4]dioxine-2-(C₂-C₄alkyl),1-(thiophen-2-yl)-1-oxo-(C₁-C₆alkyl),3-oxo-2H-benzo[b][1,4]oxazin-4-yl))(C₂-C₄alkyl),(2-(cycloalkyl)-1H-benzo[d]imidazol-1-yl)(C₂-C₄alkyl),((3-((C₁-C₆alkyl)carbonyloxy(methyl))-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl))(C₂-C₄alkyl),((3-(methoxycarbonylethyl)-2-oxo-2,3-dihydro-1H-benzo[c/]imidazol-1-yl))(C₂-C₄alkyl),((2-(t-butoxycarbonyl)-2,3-dihydro-1H-benzo[c/]imidazol-1-yl))(C₂-C₄alkyl), 1H-indazol-3-yl(C₂-C₄ alkyl),(1-(indolin-1-yl)-1-oxo)(C₂-C₄alkyl),((3-(C₁-C₆alkyl)oxycarbonyl(C₁-C₆alkyl))-1H-indol-1-yl)(C₂-C₄alkyl), or(2-(C₁-C₆alkyl)oxycarbonyl-1H-indol-1-yl)(C₂-C₄alkyl) R₂ is phenyloptionally para-substituted with chloro, fluoro or methoxy, linear orbranched C₂-C₆ alkyl, cycloalkyl of three to seven carbon atomsoptionally substituted with one to six halogens; R₃ is

wherein n is 3-5,

and R₁₀ is H or alkyl of one to six carbons.
 2. The compound of claim 1,wherein R₁ is (2-oxoindolin-1-yl)(C₂-C₄alkyl) optionally substituted atthe 3-position with one or two components chosen from methyl or fluoro,(3-spirocyclopropane-(2-oxoindolin-1-yl))(C₂-C₄alkyl), or(2-oxoindolin-3-yl))(C₂-C₄alkyl).
 3. The compound of claim 1, wherein R₃is represented by formula A, C, D, or F and R₁₀ is H.
 4. The compound ofclaim 3, wherein R₃ is represented by formula A or D.
 5. The compound ofclaim 1, wherein R₂ is phenyl or cyclohexyl.
 6. The compound of claim 5,wherein R₂ is cyclohexyl.
 7. The compound of claim 5, wherein R₂ isphenyl.
 8. The compound of claim 1, wherein R₁ is(2-oxoindolin-1-yl)propyl optionally substituted at the 3-position withone or two components chosen from methyl or fluoro,(3-spirocyclopropane-(2-oxoindolin-1-yl))propyl, or(2-oxoindolin-3-yl))propyl.
 9. The compound of claim 1, wherein R₁ is(2-oxoindolin-1-yl)propyl optionally substituted at the 3-position withone or two components chosen from methyl or fluoro, or(3-spirocyclopropane-(2-oxoindolin-1-yl))propyl,(2-oxoindolin-3-yl))propyl; R₂ is phenyl or cyclohexyl; and R₃ isrepresented by formula A, C, D, or F and R₁₀ is H.
 10. The compound ofclaim 9, wherein R₁ is (2-oxoindolin-1-yl)propyl and R₂ is cyclohexyl.11. The compound of claim 10, wherein R₃ is represented by formula A.12. A compound of claim 1 chosen from the group consisting of3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

(R)-2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylaceticacid

(S)-2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylaceticacid

3-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

3-((1-cyclohexyl-4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, formate

3-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, hydrochloride

3-((4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid, hydrochloride salt

3-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

3-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

2-((4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

2-((4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

2-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

2-((1-(4-Fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid

2-((8-(3-(3-Fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoicacid


13. A composition comprising a compound of claim 1 and at least onepharmaceutically acceptable excipient.
 14. A method for treating a humanpatient having a condition that is responsive to D₂ or D₃ antagonistactivity, which method comprises administering a compound of claim 1 tothe patient in need of such treatment.
 15. The method according to claim14, wherein a gastrointestinal prokinetic drug is coadministered. 16.The method according to claim 15, wherein the gastrointestinalprokinetic drug is prucalopride, naronapride, cisapride, mosapride,velusetrag, or tegaserod.
 17. (canceled)
 18. A method for treating pain,the method comprising administering a compound of claim 1 with an opioidanalgesic to a patient in need of such treatment.
 19. The methodaccording to claim 18, wherein the opioid analgesic is selected from thegroup consisting of morphine, fentanyl, tramadol, sufentanil,alfentanil, remifentanil, carfentanil, and lofentanil.